Parkinson's Disease

Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a chronic

Parkinson's disease
degenerative disorder of the central nervous system that affects
both the motor system and non-motor systems. The symptoms Other names Parkinson disease,
usually emerge slowly, and as the disease progresses, non- idiopathic or primary
motor symptoms become more common. Early symptoms are parkinsonism,
tremor, rigidity, slowness of movement, and difficulty with hypokinetic rigid
walking. Problems may also arise with cognition, behaviour, syndrome, paralysis
sleep, and sensory systems. Parkinson's disease dementia is agitans, shaking
common in advanced stages.
palsy
The motor symptoms of the disease result from the nerve cell
death in the substantia nigra, a midbrain region that supplies
dopamine to the basal ganglia. The cause of this cell death is
poorly understood but involves the aggregation of the protein
alpha-synuclein into Lewy bodies within the neurons.
Collectively, the main motor symptoms are known as
parkinsonism. Contributing factors include a combination of
genetic and environmental factors. Those with an affected
family member are at an increased risk of getting the disease, Specialty Neurology
with certain genes known to be inheritable risk factors. Symptoms Tremor, rigidity,
Environmental risks include exposure to pesticides and prior
slowness of
head injuries; a history of exposure to trichloroethylene is also
suspected. movement, difficulty
walking[1]
Diagnosis of Parkinson's disease is mainly based on symptoms, Complications Dementia,
usually motor-related. PD typically occurs in people over the depression,
age of 60, of whom about one percent are affected. In those
anxiety,[2] eating
younger than 50, it is termed early-onset PD. The average post-
problems, and sleep
diagnosis life expectancy is 7–15 years. No cure for PD is
known, and treatment aims to mitigate symptoms. Initial problems
treatment typically includes L-DOPA, MAO-B inhibitors, or Usual onset Age over 60[1][3]
dopamine agonists. As the disease progresses, these Causes Unknown[4]
medications become less effective and produce a side effect
marked by involuntary muscle movements. Diet and certain Risk factors Pesticide exposure,
forms of rehabilitation have shown some effectiveness at head injuries[4]
improving symptoms. Surgery to place microelectrodes for Diagnostic Based on
deep brain stimulation has been used to reduce severe motor method symptoms[1]
symptoms where drugs are ineffective. Evidence for treatments
for the nonmovement-related symptoms of PD, such as sleep Differential Dementia with Lewy
disturbances and emotional problems, is less strong. diagnosis bodies, progressive
supranuclear palsy,
The disease is named after English doctor James Parkinson, essential tremor,
who published the first detailed description in An Essay on the antipsychotic use[5]
Shaking Palsy, in 1817. Public awareness campaigns include
Treatment Medications,
World Parkinson's Day and the use of a red tulip symbolizes
surgery[1]
Parkinson's awareness. People with PD who have increased Medication L-DOPA, dopamine
the public's awareness of the condition include boxer agonists[2]
Muhammad Ali and actor Michael J. Fox.
Frequency 6.2 million (2015)[6]
Deaths 117,400 (2015)[7]
Classification
Named after James Parkinson
A progressive neurodegenerative disease,[8][9] Parkinson's
disease (PD) is the most common form of parkinsonism—which encompasses tremor, bradykinesia,
rigidity, and postural instability—and is also called idiopathic parkinsonism, meaning that it has no
identifiable cause.[10][11]
Parkinson's can be classified in other ways. The parkinsonian syndromes include Parkinson's, along with
other conditions.[12] It is included among the Lewy body diseases,[13] and is a synucleinopathy, meaning
that it is characterized by abnormal deposits of alpha-synuclein protein in the brain. The synucleinopathies
include dementia with Lewy bodies, multiple system atrophy, and other rarer conditions.[14][9] Some rare
genetic forms of Parkinson's do not exhibit alpha-synuclein aggregation.[15]
Signs and symptoms

The most recognizable symptoms are movement (motor) related, and include tremor, bradykinesia
(slowness of movement), rigidity, and shuffling/stooped gait.[16] Non-motor symptoms, including
autonomic dysfunction (dysautonomia), neuropsychiatric problems (mood, cognition, behavior or thought
alterations), and sensory (especially altered sense of smell) and sleep difficulties may be present as well.
Patients may have non-motor symptoms that precede the onset of motor symptoms including constipation,
anosmia, and REM Behavior Disorder. Generally, symptoms such as dementia, psychosis, orthostasis, and
more severe falls occur later.[16] Dysphagia can begin at any time during the course of Parkinson's, and
affects more than 80% of patients.[17][18]
Motor
Four motor symptoms are

considered as cardinal signs in
PD: tremor, slowness of
movement (bradykinesia),
rigidity, and postural
instability.[16]
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.[16] It typically appears in
only one hand, eventually
affecting both hands as the
disease progresses.[16] [19]
Features of Parkinsonian gait (more obvious in the side view).
Frequency of PD tremor is
between 4–6 hertz (cycles per
second). A common characteristic of tremor is pill-rolling, the tendency of the index finger and thumb to
touch and perform together with a circular movement.[16][20] The term derives from the similarity between
the movement of people with PD and the early pharmaceutical technique of manually making pills.[20]
Bradykinesia 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, presenting as 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, people with PD can ride a bicycle or climb stairs more easily than walk on the level.
Although most physicians may readily notice bradykinesia, formal assessment requires persons to do
repetitive movements with their fingers and feet.[21]
In parkinsonism, rigidity or hypokinesia can be uniform, known as lead-pipe rigidity, or ratcheted, known
as cogwheel rigidity.[10][16][22][23] The combination of tremor and increased tone is considered to be at the
origin of cogwheel rigidity.[24] Rigidity may be associated with joint pain; such pain being a frequent initial
manifestation of the disease.[16] In early stages of PD, rigidity is asymmetrical and tends to affect the neck
and shoulder muscles before the muscles of the face and extremities.[25] 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,[26] and secondarily to bone fractures, loss of confidence, and reduced mobility.[27] Instability is absent
in the initial stages, especially in younger people, especially before the development of bilateral
symptoms.[28] 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.[16]
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). Other common
signs include 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.[29] Although individuals with PD typically have motor symptoms
predominantly on one side of the body, mask-like facial expression can occur on both sides of the face.[30]
Cognitive
PD causes neuropsychiatric disturbances ranging from mild to severe including disorders of cognition,
mood, behavior, and thought.[16] Cognitive disturbances can occur in the early stages or before diagnosis,
and increase in prevalence with duration of the disease.[16][31] The most common cognitive deficit 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.[31][32] Other cognitive difficulties include slowed cognitive processing speed, impaired
recall, and impaired perception and estimation of time.[31][32] Nevertheless, improvement appears when
recall is aided by cues.[31] Visuospatial difficulties are a 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.[31][32]
A person with PD has two to six times the risk of dementia compared with the general population.[16][31]
Up to 78% of people with PD have Parkinson's disease dementia.[33] The prevalence of dementia increases
with age, and to a lesser degree, duration of the disease.[34] 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.[31]
Psychosis
Psychosis can be considered a symptom with a prevalence from 26 to 83%.[35][36] Hallucinations or

delusions occur in about 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 or someone standing 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. Psychosis is believed to
be an integral part of the disease. A psychosis with delusions and associated delirium is a recognized
complication of anti-Parkinson drug treatment. Urinary tract infections (frequent in the elderly) and
underlying brain pathology or changes in neurotransmitters or their receptors (e.g., acetylcholine, serotonin)
are thought to play a role in psychosis in PD.[37][38]
Neuropsychiatric
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.[16] Depression impacts an estimated 20% to 35% of patients, and may
appear at any stage of the disease. It can manifest with symptoms common to the disease process (fatigue,
insomnia, and difficulty with concentration), which makes diagnosis difficult. The imbalance and changes
in dopamine, serotonin, and noradrenergic hormones and functional impairment are causes of depression in
PD-affected people.[35][39] Suicidal ideation is higher than in the general population, but suicidal attempts
themselves are lower.[35][39] Risk factors for depression include disease onset under age 50, being female,
previous history of depression, or severe motor symptoms.[35]
Anxiety has been estimated to have a prevalence in PD-affected people usually around 30–40% and up to
60% has been found.[35][39] Anxiety with PD is complex and consists of symptoms specific to PD.[40]
Anxiety can be higher during motor "off" periods (times when medication is ineffective) and is likely to be
diagnosed after diagnosis due to dysfunction of neurotransmitter pathways.[40] PD-affected people
experience panic attacks more frequently compared with the general population. Both anxiety and
depression have been found to be associated with decreased quality of life.[35][41] Symptoms can range
from mild and episodic to chronic with potential causes being abnormal gamma-aminobutyric acid levels
and embarrassment or fear about symptoms or disease.[35][41] Risk factors for anxiety in PD are disease
onset under age 50, women, and off periods.[35] No standard treatment for PD-associated anxiety exists.[40]
Apathy and anhedonia can be defined as a loss of motivation and an impaired ability to experience
pleasure[42] and are symptoms classically associated with depression, but differ in PD-affected people in
treatment and mechanism. Apathy presents in around 16.5–40%. Symptoms of apathy include reduced
initiative/interests in new activities or the world around them, emotional indifference, and loss of affection
or concern for others.[35] Apathy is associated with deficits in cognitive functions including executive and
verbal memory.[39] Anhedonia occurs in 5–75% of people with PD, depending on the study population
assessed and overlap with apathy.[43]
Impulse-control disorders, including pathological gambling, compulsive sexual behavior, binge eating,
compulsive shopping, and reckless generosity, can be medication-related, particularly orally active
dopamine agonists. The dopamine dysregulation syndrome – with wanting of medication contributing to
overuse – is a rare complication of levodopa use.[44]
Punding, complicated, repetitive, aimless, stereotyped behaviors, is another side effect of anti-Parkinson
medication.
Gastrointestinal
Gastrointestinal issues in Parkinson's disease include constipation, impaired stomach emptying (gastric
dysmotility), and excessive production of saliva can be severe enough to cause discomfort or endanger
health.[45][46] Other upper gastrointestinal symptoms include swallowing impairment (Oropharyngeal
dysphagia) and small intestinal bacterial overgrowth.[47]
Individuals with Parkinson's have alpha-synuclein deposits in the digestive tract as well as the brain.[47]
Constipation is one of the symptoms associated with an increased risk of PD and may precede diagnosis of
PD.[47]
Other
Sleep disorders occur with PD and can be worsened by medications.[16] Symptoms can manifest as
daytime drowsiness (including sudden sleep attacks resembling narcolepsy), disturbances in Rapid eye
movement sleep, or insomnia.[16] REM behavior disorder may begin years before the development of
motor or cognitive elements of PD or dementia with Lewy bodies.[48]
Alterations in the autonomic nervous system can lead to orthostatic hypotension (low blood pressure on
standing), oily skin, excessive sweating, urinary incontinence, and altered sexual function.[16]
Changes in perception may include an impaired sense of smell, disturbed vision, pain, and paresthesia
(tingling and numbness).[16] These symptoms can occur years before diagnosis of the disease.[16]
Causes
None of the proposed risk factors have been conclusively proven.[49] The most frequently replicated
relationships are an increased risk in those exposed to pesticides and a reduced risk in smokers.[49][50]
Research indicates that PD results from a complex interaction between genetic and environmental
factors.[4] Only a small minority of cases can be attributed solely to genetic causes. Moreover, as idiopathic
PD can last and progress over decades, the timing of exposure factor may influence the progression or
severity of certain stages.[51] Statistically significant geographical clusters of Parkinson's cases have been
reported, suggesting a common environmental cause that is either chemical or infectious.[52]
Genetic
Research indicates that PD results from a complex interaction between genetic and environmental
factors.[4] Around 15% of diagnosed individuals have a first-degree relative who has the disease,[10] and 5–
10% have a mutation in genes.[53][54] Harboring one of these gene mutations may not lead to the disease;
susceptibility factors put them at an increased risk, in combination with other factors, which affect age of
onset, severity and progression.[53] At least 11 autosomal dominant and nine autosomal recessive gene
mutations have been implicated in the development of PD. The autosomal dominant genes include SNCA,
PARK3, UCHL1, LRRK2, GIGYF2, HTRA2, EIF4G1, TMEM230, CHCHD2, RIC3, and VPS35.
Autosomal recessive genes include PRKN, PINK1, DJ-1,
ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, and VPS13C.
Some genes are X-linked or have unknown inheritance pattern;
those include USP24, PARK12, and PARK16. A 22q11 deletion is
known to be associated with PD.[55][54] An autosomal dominant
form has been associated with mutations in the LRP10 gene.[56][57]
About 5% of people with PD have mutations in the GBA1

gene.[58] These mutations are present in fewer than 1% of the
unaffected population. The risk of developing PD is increased 20– Parkin crystal structure
30-fold if these mutations are present. PD associated with these
mutations has the same clinical presentation, but an earlier age of
onset and a more rapid cognitive and motor decline. This gene encodes glucocerebrosidase. Low levels of
this enzyme cause Gaucher's disease.
Alpha-synuclein, a protein encoded by SNCA gene mutations, is the main component of the Lewy bodies
that accumulate in the brains of people with PD.[53] Alpha-synuclein activates ataxia telangiectasia mutated,
a major DNA damage-repair signaling kinase.[59] In addition, alpha-synuclein activates the non-
homologous end joining DNA repair pathway. The aggregation of alpha-synuclein in Lewy bodies appears
to be a link between reduced DNA repair and brain-cell death in PD.[59]
Mutations in some genes, including SNCA, LRRK2, and GBA, have been found to be risk factors for
sporadic (nonfamilial) PD.[53] Mutations in the gene LRRK2 are the most common known cause of familial
and sporadic PD, accounting for around 5% of individuals with a family history of the disease and 3% of
sporadic PD.[60][53] A mutation in GBA presents the greatest genetic risk of developing Parkinsons
disease.[61]
Parkinson-related genes are involved in the function of lysosomes, organelles that digest cellular waste
products. Lysosomal disorders that reduce the ability of cells to break down alpha-synuclein may cause
PD.[62]
Non-genetic
Chemical and medicational
Multi-decade studies have identified an increased likelihood of Parkinson's in association with agricultural
work,[63][64] pesticide (e.g., paraquat[65][66]) exposure, and rural habitation. Moreover, chlorinated solvents
—used in various commercial and industrial application like dry cleaning and degreasing—are also
associated with increased PD risk, particularly trichloroethylene.[63][64]
Carbon disulfide is another risk factor, and has been identified in industrial worker case studies and has
induced parkinsonism in mice.[67] Manganese, which has induced Parkinson's-like pathology in mice, is
also associated with a higher risk. Welders are at a higher PD risk, tentatively from manganese fumes.
Moreover, exposure to suspended particles from traffic fumes is also associated with PD.[64]
Non-genetic Parkinson's risk factors include industrial and agricultural chemicals like carbon disulfide (left) and
traumatic brain injuries (right).
Some medical drugs are also implicated in parkinsonism. Drug-induced parkinsonism is normally reversible
by stopping the offending agent,[15] such as phenothiazines, butyrophenones, metoclopramide, and
Tetrabenazine. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a drug known for causing
irreversible parkinsonism that is commonly used in animal-model research.[15][68][69] Low concentrations
of urate in the blood are associated with an increased risk.[70]
Biological
Traumatic brain injuries (TBIs) are strongly implicated as risk factors for PD,[71] although the association
may be distorted due to recall bias and sampling bias in retrospective studies.[72] Possibly due to the
recurrent head impacts, playing American football for a longer period and at higher levels is associated with
higher PD risk.[73] Veterans are also at a higher risk. Proposed mechanisms by which TBIs could induce or
accelerate Parkinson's include alpha-synuclein accumulation, inflammation, and metabolic
dysregulation.[71]
Vascular parkinsonism is the phenomenon of the presence of Parkinson's disease symptoms combined with
findings of vascular events (such as a cerebral stroke). The damaging of the dopaminergic pathways is
similar in cause for both vascular parkinsonism and idiopathic PD, and so present with similar symptoms.
Differentiation can be made with careful bedside examination, history evaluation, and imaging.[74][15][75]
A possible link exists between PD and Helicobacter pylori infection that can prevent the absorption of
some drugs, including levodopa.[76][77]
Psychological
Behavioral and psychological factors have also been associated with risk of PD. For example, a meta-
analysis found that neuroticism was associated with higher risk of incident PD.[78] Similarly, in a sample of
about a half million individuals found that adults who reported being lonely had a greater risk of developing
PD over a 15 years of follow-up.[79]
Pathophysiology
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 (structure at right).
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).[60] In
Parkinson's disease, alpha-synuclein becomes misfolded and clump together with other alpha-synuclein.
Cells are unable to remove these clumps, and the alpha-synuclein becomes cytotoxic, damaging the
cells.[80][81] These clumps can be seen in neurons under a microscope and are called Lewy bodies. Loss of
neurons is accompanied by the death of astrocytes (star-shaped glial cells) and an increase in the number of
microglia (another type of glial cell) in the substantia nigra.[82] Severity of progression of the parts of the
brain affected by PD can be measured with Braak staging. According to this staging, PD starts in the
medulla and the olfactory bulb before moving to the substantia nigra pars compacta and the rest of the
midbrain/basal forebrain. Movement symptom onset is associated when the disease begins to affect the
substantia nigra pars compacta.[83]
Five major pathways in the brain connect other brain areas to the basal ganglia. These are known as the
motor, oculomotor, associative, limbic, and orbitofrontal circuits. Names indicate the main projection area of
each circuit.[85] All are affected in PD, and their disruption causes movement-, attention- and learning-
related symptoms of the disease.[85] Scientifically, the motor circuit has been examined the most
intensively.[85]
Since 1980, a particular conceptual model of the motor circuit and its alteration with PD has been of
influence although some limitations have been pointed out which have led to modifications.[85] 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. The result of dopamine depletion is to produce hypokinesia, an overall
reduction in motor output.[85] 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.[85]
Brain cell death
One mechanism causing brain cell death results from abnormal

accumulation of the protein alpha-synuclein bound to ubiquitin in
damaged cells. This insoluble protein accumulates inside neurons
forming inclusions, known as Lewy bodies.[60][86] These bodies
first appear in the olfactory bulb, medulla oblongata and pontine A. Schematic initial
tegmentum; individuals at this stage may be asymptomatic or have progression of Lewy body
early nonmotor symptoms (such as loss of sense of smell or some deposits in the first stages
sleep or automatic dysfunction). As the disease progresses, Lewy of PD, as proposed by
bodies develop in the substantia nigra, areas of the midbrain and Braak and colleagues
basal forebrain, and finally, the neocortex.[60] These brain sites are B. Localization of the area of
the main places of neuronal degeneration in PD, but Lewy bodies significant brain volume
may be protective from cell death (with the abnormal protein reduction in initial PD
sequestered or walled off). Other forms of alpha-synuclein (e.g. compared with a group of
oligomers) that are not aggregated into Lewy bodies and Lewy participants without PD[84]
neurites, may in fact be the toxic forms of the protein.[87][86] 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 uncommon
unless the person has dementia.[82]
Other mechanisms include proteasomal and lysosomal systems

dysfunction and reduced mitochondrial activity.[87] 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
An illustration of the dopamine
mechanisms are obscure.[88] pathways throughout the brain
Neuroimmune interaction
The neuroimmune interaction is heavily implicated in PD pathology. PD and autoimmune disorders share
genetic variations and molecular pathways. Some autoimmune diseases may even increase one's risk of
developing PD, up to 33% in one study.[89] Autoimmune diseases linked to protein expression profiles of
monocytes and CD4+ T cells are linked to PD. Herpes virus infections can trigger autoimmune reactions to
alpha-synuclein, perhaps through molecular mimicry of viral proteins.[90] Alpha-synuclein, and its
aggregate form, Lewy bodies, can bind to microglia. Microglia can proliferate and be over-activated by
alpha-synuclein binding to MHC receptors on inflammasomes, bringing about a release of proinflammatory
cytokines like IL-1β, IFNγ, and TNFα.[91]
Activated microglia influence the activation of astrocytes, converting their neuroprotective phenotype to a
neurotoxic one. Astrocytes in healthy brains serve to protect neuronal connections. In PD patients,
astrocytes cannot protect the dopaminergic connections in the striatum. Microglia present antigens via
MHC-I and MHC-II to T cells. CD4+ T cells, activated by this process, are able to cross the blood brain
barrier (BBB) and release more proinflammatory cytokines, like interferon-γ (IFNγ), TNFα, and IL-1β.
Mast cell degranulation and subsequent proinflammatory cytokine release is implicated in BBB breakdown
in PD. Another immune cell implicated in PD are peripheral monocytes and have been found in the
substantia nigra of PD patients. These monocytes can lead to more dopaminergic connection breakdown. In
addition, monocytes isolated from PD patients express higher levels of the PD-associated protein, LRRK2,
compared with non-PD individuals via vasodilation.[92] In addition, high levels of pro-inflammatory
cytokines, such as IL-6, can lead to the production of C-reactive protein by the liver, another protein
commonly found in PD patients, that can lead to an increase in peripheral inflammation.[93][94]
Peripheral inflammation can affect the gut-brain axis, an area of the body highly implicated in PD. PD
patients have altered gut microbiota and colon problems years before motor issues arise.[93][94] Alpha-
synuclein is produced in the gut and may migrate via the vagus nerve to the brainstem, and then to the
substantia nigra.[95] Furthermore, the bacteria Proteus mirabilis has been associated with higher levels of
alpha-synuclein and an increase of motor symptoms in PD patients.[96]
Diagnosis
Physician's initial assessment is typically based on medical history and neurological examination.[16] They
assess motor symptoms (bradykinesia, rest tremors, etc.) using clinical diagnostic criteria. 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 diverge from PD, requiring that presentation is periodically
reviewed to confirm the accuracy of the diagnosis.[16][97]
Multiple causes can occur for parkinsonism or diseases that look similar. Stroke, certain medications, and
toxins can cause "secondary parkinsonism" and need to be assessed during visit.[83][97] Parkinson-plus
syndromes, such as progressive supranuclear palsy and multiple system atrophy, must be considered and
ruled out appropriately to begin a different treatment and disease progression (anti-Parkinson's medications
are typically less effective at controlling symptoms in Parkinson-plus syndromes).[16] 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.[98]
Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process,
especially in the early stages of the disease. The most widely known criteria come from the UK Queen
Square Brain Bank for Neurological Disorders and the U.S. National Institute of Neurological Disorders
and Stroke. 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 symptoms 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, the clinical course of at least ten years and appearance of dyskinesias
induced by the intake of excessive levodopa.[99] Assessment of sudomotor function through
electrochemical skin conductance can be helpful in diagnosing dysautonomia.[100]
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 refining diagnoses at follow-up examinations.
When clinical diagnoses performed mainly by nonexperts are checked by autopsy, the average accuracy is
73.8%. Overall, 80.6% of PD diagnoses are accurate, and 82.7% of diagnoses using the Brain Bank criteria
are accurate.[101]
Imaging
Computed tomography (CT) scans of people with PD usually appear normal.[102] Magnetic resonance
imaging has become more accurate in diagnosis of the disease over time, specifically through iron-sensitive
T2* and susceptibility weighted imaging 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.[103] In a meta-analysis, absence of this pattern was highly sensitive and specific for the
disease.[104] A meta-analysis found that neuromelanin-MRI can discriminate individuals with Parkinson's
from healthy subjects.[105] Diffusion MRI has shown potential in distinguishing between PD and
Parkinson-plus syndromes, as well as between PD motor subtypes,[106] though its diagnostic value is still
under investigation.[102] CT and MRI are 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.[102]
The metabolic activity of dopamine transporters in the basal ganglia can be directly measured with positron
emission tomography and single-photon emission computed tomography scans. It has shown high
agreement with clinical diagnoses of PD.[107] Reduced dopamine-related activity in the basal ganglia can
help exclude drug-induced Parkinsonism. This finding is nonspecific and can be seen with both PD and
Parkinson-plus disorders.[102] In the United States, DaTSCANs are only FDA approved to distinguish PD
or Parkinsonian syndromes from essential tremor.[108]
Iodine-123-meta-iodobenzylguanidine myocardial scintigraphy can help locate denervation of the muscles

of the heart which can support a PD diagnosis.[83]
Differential diagnosis
Secondary parkinsonism – The multiple causes of parkinsonism can be differentiated through careful
history, physical examination, and appropriate imaging.[15][83][109] This topic is further discussed in the
causes section here.
Other Parkinson-plus syndromes can have similar movement symptoms but have a variety of associated
symptoms. Some of these are also synucleinopathies. Lewy body dementia involves motor symptoms with
early onset of cognitive dysfunction and hallucinations which precede motor symptoms. Alternatively,
multiple systems atrophy or MSA usually has early onset of autonomic dysfunction (such as orthostasis),
and may have autonomic predominance, cerebellar symptom predominance, or Parkinsonian
predominance.[110]
Other Parkinson-plus syndromes involve tau, rather than alpha-synuclein. These include progressive
supranuclear palsy (PSP) and corticobasal syndrome (CBS). PSP predominantly involves rigidity, early
falls, bulbar symptoms, and vertical gaze restriction; it can be associated with frontotemporal dementia
symptoms. CBS involves asymmetric parkinsonism, dystonia, alien limb, and myoclonic jerking.[111]
Presentation timelines and associated symptoms can help differentiate similar movement disorders from
idiopathic Parkinson disease.
Parkinson-plus syndrome – Multiple diseases can be considered part of the Parkinson's plus group,
including corticobasal syndrome, multiple system atrophy, progressive supranuclear palsy, and dementia
with Lewy bodies. Differential diagnosis can be narrowed down with careful history and physical exam
(especially focused on the sequential onset of specific symptoms), progression of the disease, and response
to treatment.[112][109] Some key symptoms:[15][109]
Corticobasal syndrome – levodopa-resistance, myoclonus, dystonia, corticosensory loss,

apraxia, and non-fluent aphasia
Dementia with Lewy bodies – levodopa resistance,
cognitive predominance before motor symptoms, and
fluctuating cognitive symptoms, (visual hallucinations
are common in this disease)
Essential tremor – This can at first look like
parkinsonism, but has key differentiators. In essential
tremor, the tremor gets worse with action (improves in
PD), a lack of other symptoms is common in PD, and
normal DatSCAN is seen.[109][15]
Multiple system atrophy – levodopa resistance, rapidly
progressive, autonomic failure, stridor, present Babinski
sign, cerebellar ataxia, and specific MRI findings
Progressive supranuclear palsy – levodopa resistance,
restrictive vertical gaze, specific MRI findings, and early Hot Cross Bun sign that is
and different postural difficulties commonly found in MRI of multiple
system atrophy
Other conditions that can have similar presentations to PD
include:[113][15]
Arthritis
Creutzfeldt–Jakob disease
Depression
Dystonia
Fragile X-associated tremor/ataxia syndrome
Frontotemporal dementia and parkinsonism linked to chromosome 17
Huntington's disease
Idiopathic basal ganglia calcification
Neurodegeneration with brain iron accumulation
Normal-pressure hydrocephalus
Obsessional slowness
Psychogenic parkinsonism
Wilson's disease
Prevention
Exercise in middle age may reduce the risk of PD later in life.[114] Caffeine appears protective with a
greater decrease in risk occurring with a larger intake of caffeinated beverages such as coffee.[115]
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 shown.[49] The results regarding fat and
fatty acids have been contradictory.[49] Use of nonsteroidal anti-inflammatory drugs (NSAIDs) and calcium
channel blockers may be protective.[4] A 2010 meta-analysis found that NSAIDs (apart from aspirin), have
been associated with at least a 15% (higher in long-term and regular users) reduction in the incidence of the
development of PD.[116] As of 2019 meta-analyses have failed to confirm this link. Multiple studies have
demonstrated a link between the use of ibuprofen and a decreased risk of Parkinson's development.[117]
Management
No cure for Parkinson's disease is known. Medications, surgery, and physical treatment may provide relief,
improve the quality of a person's life, and are much more effective than treatments for other neurological
disorders such as Alzheimer's disease, motor neuron disease, and Parkinson-plus syndromes.[118] The main
families of drugs useful for treating motor symptoms are levodopa always combined with a dopa
decarboxylase inhibitor and 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.[118]
Braak staging of PD uses six stages that can identify early, middle, and late stages.[119] The initial stage in
which some disability has already developed and requires pharmacological treatment is followed by later
stages 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.[119]
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.[120] Levodopa is still the most effective treatment for the motor symptoms of PD and
treatment should be prompt in people when their quality of life is impaired. Levodopa-related dyskinesias
correlate more strongly with duration and severity of the disease than duration of levodopa treatment.[121]
In later stages, the aim is to reduce PD symptoms, while controlling fluctuations in the effect of the
medication. Sudden withdrawals from medication or its overuse must be managed.[120] When oral
medications are inadequate in controlling symptoms, surgery (deep brain stimulation or high-intensity
focused ultrasound[122]), subcutaneous waking-day apomorphine infusion, and enteral dopa pumps may be
useful.[123] Late-stage PD presents challenges requiring a variety of treatments, including those for
psychiatric symptoms particularly depression, orthostatic hypotension, bladder dysfunction, and erectile
dysfunction.[123] In the final stages of the disease, palliative care is provided to improve a person's quality
of life.[124]
A 2020 Cochrane review found no certain evidence that cognitive training is beneficial for people with
Parkinson's disease, dementia or mild cognitive impairment.[125] The findings are based on low certainty
evidence of seven studies.
Medications
Levodopa
Levodopa is usually the first drug of choice when treating

Parkinson's disease and has been the most widely used PD
treatment since the 1980s.[120][126] The motor symptoms of PD are
the result of reduced dopamine production in the brain's basal
ganglia. Dopamine fails to cross the blood–brain barrier so it cannot
be taken as a medicine to boost the brain's depleted levels of
LCE pills, containing Levodopa,
dopamine. A precursor of dopamine, levodopa, can pass through to
carbidopa, and entacapone
the brain where it is readily converted to dopamine. Administration
of levodopa temporarily diminishes the motor symptoms of PD.
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
orthostatic hypotension.[127] Carbidopa and benserazide are dopa decarboxylase inhibitors that fail to 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 and is available combined with levodopa in the same pill.[128]
Prolonged use of levodopa is associated with the development of complications, such as involuntary
movements (dyskinesias) and fluctuations in the impact of the medication.[120] 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 increased PD symptoms (off state).[120][129] Using lower
doses of levodopa may reduce the risk and severity of these levodopa-induced complications.[130] A former
strategy, called "drug holidays", to reduce levodopa-related dyskinesia and fluctuations was to withdraw
levodopa medication for some time[126] which can bring on dangerous side effects such as neuroleptic
malignant syndrome and is discouraged.[120] Most people with PD eventually need levodopa and later
develop levodopa-induced fluctuations and dyskinesias.[120] Adverse effects of levodopa, including
dyskinesias, mistakenly influence patients and providers to delay treatment which reduces potential for
optimal results.
Levodopa by itself is available in oral (tablets and capsules), oral inhalation, and infusion form. Inhaled
levodopa can be used when oral levodopa therapy has reached a point where "off" periods have increased
in length.[131][132][133]
COMT inhibitors
During the course of PD, affected people can experience a

wearing-off phenomenon, where a recurrence of symptoms occurs
after a dose of levodopa, but right before their next dose.[83]
Catechol-O-methyltransferase (COMT) is a protein that degrades
levodopa before it can cross the blood–brain barrier and COMT
inhibitors allow for more levodopa to cross.[135] They are normally
used in the management of later symptoms, but can be used in
conjunction with levodopa/carbidopa when a person is
COMT metabolizes levodopa to 3-O-
experiencing the wearing off-phenomenon with their motor
methyldopa. COMT inhibitors help
symptoms.[83][126] stop this reaction, allowing for more
levodopa to cross the blood–brain
Three COMT inhibitors are used to treat adults with PD and end-
barrier and become dopamine where
of-dose motor fluctuations – opicapone, entacapone, and
it is needed.[134]
tolcapone.[83] Tolcapone has been available for but its usefulness is
limited by possible liver damage complications requiring liver-
function monitoring.[136][15][83][135] Entacapone and opicapone cause little alteration to liver
function.[135][137][138] Licensed preparations of entacapone contain entacapone alone or in combination
with carbidopa and levodopa.[139][15][140] Opicapone is a once-daily COMT inhibitor.[141][83]
Dopamine agonists
Dopamine agonists that bind to dopamine receptors in the brain have similar effects to levodopa.[120] These
were initially used as a complementary therapy to levodopa for individuals experiencing levodopa
complications (on-off fluctuations and dyskinesias); they are mainly used on their own as first therapy for
the motor symptoms of PD with the aim of delaying the initiation of levodopa therapy, thus delaying the
onset of levodopa's complications.[120][142] 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
effective enough to manage these symptoms in the first years of treatment.[10] 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.[10] Thus, dopamine agonists are the preferred initial treatment for
younger-onset PD, and levodopa is preferred for older-onset PD.[10]
Dopamine agonists produce side effects, including drowsiness, hallucinations, insomnia, nausea, and
constipation.[120][126] Side effects appear with minimal clinically effective doses giving the physician
reason to search for a different drug.[120] Agonists have been related to impulse-control disorders (such as
increased sexual activity, eating, gambling, and shopping) more strongly than other antiparkinson
medications.[143][126]
Apomorphine, a dopamine agonist, may be used to reduce off periods and dyskinesia in late PD.[120] It is
administered only by intermittent injections or continuous subcutaneous infusions.[120] Secondary effects
such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be
closely monitored.[120] Two dopamine agonists administered through skin patches (lisuride and rotigotine)
are useful for people in the initial stages and possibly to control off states in those in advanced states.[8] Due
to an increased risk of cardiac fibrosis with ergot-derived dopamine agonists (bromocriptine, cabergoline,
dihydroergocryptine, lisuride, and pergolide), they should only be considered for adjunct therapy to
levodopa.[126]
MAO-B inhibitors
MAO-B inhibitors (safinamide, selegiline and rasagiline) increase the amount of dopamine in the basal
ganglia by inhibiting the activity of monoamine oxidase B, an enzyme that breaks down dopamine.[120]
They have been found to help alleviate motor symptoms when used as monotherapy (on their own); when
used in conjunction with levodopa, time spent in the off phase is reduced.[144][126] Selegiline has been
shown to delay the need for beginning levodopa, suggesting that it might be neuroprotective and slow the
progression of the disease.[145] An initial study indicated that selegiline in combination with levodopa
increased the risk of death, but this has been refuted.[146]
Common side effects are nausea, dizziness, insomnia, sleepiness, and (in selegiline and rasagiline)
orthostatic hypotension.[145][83] MAO-Bs are known to increase serotonin and cause a potentially
dangerous condition known as serotonin syndrome.[145]
Other drugs
Other drugs such as amantadine may be useful as treatment of motor symptoms, but evidence for use is
lacking.[120][147] Anticholinergics should not be used for dyskinesia or motor fluctuations but may be
considered topically for drooling.[126] A diverse range of symptoms beyond those related to motor function
can be treated pharmaceutically.[148] Examples are the use of quetiapine or clozapine for psychosis,
cholinesterase inhibitors or memantine for dementia, and modafinil for excessive daytime
sleepiness.[148][149][126] In 2016, pimavanserin was approved for the management of PD psychosis.[150]
Doxepin and rasagline may reduce physical fatigue in PD.[151]
Surgery
Treating motor symptoms with surgery was once a common practice but
the discovery of levodopa has decreased the amount of procedures.[152]
Studies have led to great improvements in surgical techniques, so surgery
can be used in people with advanced PD for whom drug therapy is no
longer sufficient.[152] 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, globus pallidus, or subthalamic nucleus.[152] DBS
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 lacking severe neuropsychiatric problems.[153] 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 Placement of an electrode
into the brain: the head is
dyskinesia.[152]
stabilised in a frame for
Four areas of the brain have been treated with neural stimulators in stereotactic surgery.
PD.[154] These are the globus pallidus interna, thalamus, subthalamic
nucleus, and pedunculopontine nucleus. DBS of the globus pallidus interna
improves motor function, while DBS of the thalamic DBS improves tremor, but has little impact on
bradykinesia or rigidity. DBS of the subthalamic nucleus is usually avoided if a history of depression or
neurocognitive impairment is present. DBS of the subthalamic nucleus is associated with a reduction in
medication. Pedunculopontine nucleus DBS remains experimental at present. Generally, DBS is associated
with 30–60% improvement in motor score evaluations.[155]
Rehabilitation
Exercise programs are recommended in people with PD.[114] Some evidence shows that speech or mobility
problems can improve with rehabilitation, although studies are scarce and of low quality.[156][157] Regular
physical exercise with or without physical therapy can be beneficial to maintain and improve mobility,
flexibility, strength, gait speed, and quality of life.[157] When an exercise program is performed under the
supervision of a physiotherapist, more improvements occur in motor symptoms, mental and emotional
functions, daily living activities, and quality of life compared with a self-supervised exercise program at
home.[158] Clinical exercises may be an effective intervention targeting overall well-being of individuals
with Parkinson's. Improvement in motor function and depression may happen.[159]
In 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.[160] As for gait and addressing the
challenges associated with the disease such as hypokinesia, shuffling, and decreased arm swing,
physiotherapists have a variety of strategies to improve functional mobility and safety. Areas of interest
concerning gait during rehabilitation programs focus on improving gait speed, the base of support, stride
length, and trunk and arm-swing movement. Strategies include using 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).[161] Strengthening exercises have shown
improvements in strength and motor function for people with primary muscular weakness and weakness
related to inactivity with mild to moderate PD, but reports show an interaction between strength and the
time the medications were taken. Therefore, people with PD should perform exercises 45 minutes to one
hour after medications when they are capable.[162] Deep diaphragmatic breathing exercises are beneficial in
improving chest-wall mobility and vital capacity decreased by a forward flexed posture and respiratory
dysfunctions in advanced PD.[163] Exercise may improve constipation.[45] Whether exercise reduces
physical fatigue in PD remains unclear.[151]
Strength training exercise has been shown to increase manual dexterity in PD patients after exercising with
manual putty. This positively affects everyday life when gripping for PD patients.[164]
The Lee Silverman voice treatment (LSVT) is one of the most widely practiced treatments for speech
disorders associated with PD.[156][165] Speech therapy and specifically LSVT may improve speech.[156]
Occupational therapy (OT) aims to promote health and quality of life by helping people with the disease to
participate in a large percentage of their daily living activities.[156] Few studies have been conducted on the
effectiveness of OT, and their quality is poor, although with some indication that it may improve motor
skills and quality of life for the duration of the therapy.[156][166]
Palliative care
The goal of Palliative care is to improve quality of life for both the patient and family by providing relief
from the symptoms and stress of illnesses.[167] As Parkinson's is uncurable, treatments focus on slowing
decline and improving quality of life and are therefore palliative.[168]
Palliative care should be involved earlier, rather than later, in the disease course.[169][170] Palliative care
specialists can help with physical symptoms, emotional factors such as loss of function and jobs,
depression, fear, and existential concerns.[169][170][171]
Along with offering emotional support to both the affected person and family, palliative care addresses
goals of care. People with PD may have difficult decisions to make as the disease progresses, such as
wishes for feeding tube, noninvasive ventilator or tracheostomy, wishes for or against cardiopulmonary
resuscitation, and when to use hospice care.[168] Palliative-care team members can help answer questions
and guide people with PD on these complex and emotional topics to help them make decisions based on
values.[170][172]
Muscles and nerves that control the digestive process may be affected by PD, resulting in constipation and
gastroparesis (prolonged emptying of stomach contents).[45] A balanced diet, based on periodical nutritional
assessments, is recommended, and should be designed to avoid weight loss or gain and minimize the
consequences of gastrointestinal dysfunction.[45] As the disease advances, swallowing difficulties
(dysphagia) may appear. Using thickening agents for liquid intake and an upright posture when eating may
be useful; both measures reduce the risk of choking. Gastrostomy can be used to deliver food directly into
the stomach.[45]
Levodopa and proteins use the same transportation system in the intestine and the blood–brain barrier,
thereby competing for access.[45] Taking them together results in reduced effectiveness of the drug.[45]
Therefore, when levodopa is introduced, excessive protein consumption is discouraged in favour of a well-
balanced Mediterranean diet. In advanced stages, additional intake of low-protein products such as bread or
pasta is recommended for similar reasons.[45] To minimize interaction with proteins, levodopa should be
taken 30 minutes before meals.[45] At the same time, regimens for PD restrict proteins during breakfast and
lunch, allowing protein intake in the evening.[45]
Prognosis
PD invariably progresses with time. A severity rating method known as the Unified Parkinson's disease
rating scale (UPDRS) is the most commonly used metric for a clinical study. A modified version known as
the MDS-UPDRS is also used. An older scaling method known as the Hoehn and Yahr scale (originally
published in 1967), and a similar scale known as the Modified Hoehn and Yahr scale, have been used. The
Hoehn and Yahr scale defines five basic stages of progression.
Motor symptoms may 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 10 years. Medication has improved the prognosis of motor symptoms. In people taking
levodopa, the progression time of symptoms to a stage of high dependency from caregivers may be over 15
years. Predicting what course the disease will take for a given individual is difficult.[173] Age is an
appropriate 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 symptom onset.[87]
No hard correlation between PD progression and PD disability as a whole has been found as of 2023;
however, initial PD disability often mainly concerns the motor symptoms, whereas in later stages it is often
mainly related to the non-motor symptoms of the disease. Therapies exist that can improve or alleviate these
latter symptoms to some extent.[87] [173] As the disease advances, disability is more related to motor
symptoms that are uncontrollable by medication (such as difficulties with swallowing and dysartria, and
gait and balance problems) and to levodopa-induced complications, which appear in up to 50% of
individuals after five years of levodopa usage. Finally, after ten years most people with the disease have
autonomic disturbances, sleep problems, mood alterations and cognitive decline; these symptoms,
especially cognitive decline, greatly increase disability.[87][173]
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. A disease pattern mainly characterized by tremor as
opposed to rigidity, though, predicts an improved survival. Death from aspiration pneumonia is twice as
common in individuals with PD as in the healthy population.[173]
In 2016, PD resulted in about 211,000 deaths globally, an increase of 161% since 1990.[174] The overall
death rate increased by 19% to 1.81 per 100,000 people during that time.[174]
Epidemiology
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.[26][49][175] 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.[49][129]
The mean age of onset is around 60 years, although 5–10% begin between the ages of 20 and 50 is
classified as young onset PD.[10] Males are affected at a ratio of around 3:2 compared with females.[4] PD
may be less prevalent in those of African and Asian ancestry, although this finding is disputed.[49] The
number of new diagnoses per year of PD is between 8–18 per 100,000 person–years.[49]
China is predicted to have nearly half of the Parkinson's disease population in the world in 2030.[176] By
2040 the number of patients is expected to grow to approximately 14 million people; this growth has been
referred to as the Parkinson's pandemic.[177]
History
Early sources, including an Egyptian papyrus, an ayurvedic medical
treatise, the Bible, and Galen's writings, describe symptoms
resembling those of PD.[180] After Galen, no references
unambiguously related to PD appear until the 17th century.[180] In
the 17th and 18th centuries, Franciscus Sylvius, Hieronymus David
Gaubius, John Hunter and Auguste François Chomel wrote about
elements of the disease.[180][181][182]
In 1817, James Parkinson published his essay reporting six people

with paralysis agitans.[183] 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.[184][185] Early neurologists who made further
additions to the knowledge of the disease include Trousseau,
Gowers, Kinnier Wilson and Erb, and Jean-Martin Charcot, whose
studies between 1868 and 1881 increased the understanding of the
disease.[183] Among other advances, Charcot made the distinction
between rigidity, weakness and bradykinesia.[183] He championed Jean-Martin Charcot made
the renaming of the disease in honor of James Parkinson.[183] contributions to the understanding
of PD and proposed its name
In 1912, Frederic Lewy described microscopic particles in affected honoring James Parkinson
brains, later named Lewy bodies.[183] In 1919, Konstantin Tretiakoff
reported that the substantia nigra was the main cerebral structure
affected, but this finding was rejected until it was confirmed by
further studies published by Rolf Hassler in 1938.[183] 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.[186] In 1997, alpha-synuclein was found to be the main
component of Lewy bodies by Spillantini, Trojanowski, Goedert,
and others.[86]
Anticholinergics and surgery (lesioning of the corticospinal pathway

or some of the basal ganglia structures) were the only treatments Illustration of (advanced)
Parkinson's disease by William
until the arrival of levodopa, which reduced their use
Richard Gowers, published in
dramatically.[181][187] Levodopa was first synthesized in 1911 by
1886[178][179]
Casimir Funk, but it received little attention until the mid 20th
century.[186] It entered clinical practice in 1967 and brought about a
revolution in the management of PD.[186][188] By the late 1980s
deep brain stimulation introduced by Alim Louis Benabid and colleagues at Grenoble, France, emerged as
a possible treatment.[189]
An illustration of advanced Parkinson's disease by William Richard Gowers was published in 1886 in A
Manual of Diseases of the Nervous System, based on 1879 photographs attributed to Albert
Londe.[178][179] A new image was created in 2020 to represent diversity in levels of severity.[190][191]
Society and culture
Social impact
For some people with PD, masked facial expressions and difficulty moderating facial expressions of
emotion or recognizing other people's facial expressions can impact social well-being.[30] As the condition
progresses, tremor, other motor symptoms, difficulty communicating, or issues with mobility may interfere
with social engagement, causing individuals with PD to feel isolated.[192] Public perception and awareness
of PD symptoms such as shaking, hallucinating, slurring speech, and being off balance is lacking in some
countries and can lead to stigma.[192]
Cost
The costs of PD to society are high; in 2007, the largest share of direct cost came from inpatient care and
nursing homes, while the share coming from medication was substantially lower.[193] Indirect costs are
high, due to reduced productivity and the burden on caregivers.[193] In addition to economic costs, PD
reduces quality of life of those with the disease and their caregivers.[193]
A study based on 2017 data estimated the US economic PD burden at $51.9 billion, including direct
medical costs of $25.4 billion and $26.5 billion in indirect and non-medical costs. The projected total
economic burden surpasses $79 billion by 2037. These findings highlight the need for interventions to
reduce PD incidence, delay disease progression, and alleviate symptom burden that may reduce the future
economic burden of PD.[194]
Advocacy
The birthday of James Parkinson, 11 April, has been designated as World

Parkinson's Day.[183] A red tulip was chosen by international organizations as the
symbol of the disease in 2005; it represents the 'James Parkinson' tulip cultivar,
registered in 1981 by a Dutch horticulturalist.[195]
Advocacy organizations include the National Parkinson Foundation, which has

provided more than $180 million in care, research, and support services since
1982,[196] Parkinson's Disease Foundation, which has distributed more than Parkinson's
$115 million for research and nearly $50 million for education and advocacy awareness logo with
red tulip symbol
programs since its founding in 1957 by William Black;[197][198] the American
Parkinson Disease Association, founded in 1961;[199] and the European
Parkinson's Disease Association, founded in 1992.[200]
Notable cases
In the 21st century, the diagnosis of Parkinson's among notable figures has increased the public's
understanding of the disorder.[201]
Actor Michael J. Fox was diagnosed with PD at 29
years old,[202] and has used his diagnosis to increase
awareness of the disease.[203] To illustrate the effects of
the disease, Fox has appeared without medication in
television roles and before the United States Congress
without medication.[204] The Michael J. Fox
Foundation, which he founded in 2000, has raised over
$2 billion for Parkinson's research.[205] Boxer
Muhammad Ali showed signs of PD when he was 38,
but was undiagnosed until he was 42, and has been
called the "world's most famous Parkinson's
patient".[206] Whether he had PD or parkinsonism
related to boxing is unresolved.[207][208] Cyclist and Actor Michael J. Fox and boxer Muhammad Ali
Olympic medalist Davis Phinney, diagnosed with (center) are pictured in 2002 speaking before the
US Senate to urge increased funding for
Parkinson's at 40, started the Davis Phinney Foundation
Parkinson's research.
in 2004 to support PD research.[209][210]
At the time of his suicide in 2014, Robin Williams, the

American actor and comedian, had been diagnosed with PD[211] but his autopsy revealed dementia with
Lewy bodies.[211][212][213][214][215]
Historical figures have been theorized to have had Parkinson's,[216][217] including English philosopher
Thomas Hobbes,[218][219][220] Adolf Hitler,[221][222][217] and Mao Zedong.[223]
Research
As of 2022, no disease-modifying drugs (drugs that
target the causes or damage) are approved for
Parkinson's, so this is a major focus of Parkinson's
research.[224][225] 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.[226] To aid in
earlier diagnosis, research criteria for identifying
prodromal biomarkers of the disease have been
established.[227]
Astronaut Alexander Gerst conducting
The role of the gut–brain axis and the gut flora in PD Parkinson's research aboard the International
are recognized but the mechanism that causes Space Station in 2018
gastrointestinal symptoms is unclear.[228]
Gene therapy
Gene therapy typically involves the use of a noninfectious virus[229] to shuttle genetic material into a part of
the brain. Approaches have involved the expression of growth factors to prevent damage (Neurturin – a
GDNF-family growth factor), and enzymes such as glutamic acid decarboxylase (GAD – the enzyme that
produces GABA), tyrosine hydroxylase (the enzyme that produces L-DOPA) and catechol-O-methyl
transferase (COMT – the enzyme that converts L-DOPA to dopamine). No safety concerns have been
reported but the approaches have largely failed in phase two clinical trials.[226] The delivery of GAD
showed promise in phase two trials in 2011, but while effective at improving motor function, was inferior to
DBS. Follow-up studies in the same cohort have suggested persistent improvement.[230]
Neuroprotective treatments
A vaccine that primes the human immune system to destroy alpha-synuclein, PD01A, entered clinical trials
and a phase one report in 2020 suggested safety and tolerability.[231][232] In 2018, an antibody,
PRX002/RG7935, showed preliminary safety evidence in stage I trials supporting continuation to stage II
trials.[233]
Cell-based therapies
Beginning in the early 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.[87] These
sources of tissues have been largely replaced by induced pluripotent stem cell derived dopaminergic
neurons, as this is thought to represent a more feasible source of tissue. Initial evidence showed
mesencephalic dopamine-producing cell transplants being beneficial, but long-term benefit is
undetermined.[234] An additional problem was the excess release of dopamine by the transplanted tissue
resulting in dyskinesia.[234] In 2020, a first in human clinical trial reported the transplantation of induced
pluripotent stem cells into the brain of a person with PD.[235]
Pharmaceutical
Antagonists of adenosine receptors (specifically A2A) have been explored for Parkinson's.[236] Of these,
istradefylline has emerged as the most successful medication and was approved for medical use in the
United States in 2019.[237] It is approved as an add-on treatment to the levodopa/carbidopa regime.[237]
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External links
Parkinson's disease (https://curlie.org/Health/Conditions_and_Diseases/Neurological_Disor
ders/Parkinson%27s_Disease/) at Curlie
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