Parkinson's disease

Four motor symptoms are considered as cardinal signs in PD: tremor, slowness of movement (bradykinesia), rigidity, and postural instability.[36]

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.[36] It typically appears in only one hand, eventually affecting both hands as the disease progresses.[36] 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.[36][39] The term derives from the similarity between the movement of people with PD and the early pharmaceutical technique of manually making pills.[39]

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.[40]

In parkinsonism, rigidity or hypokinesia can be uniform, known as lead-pipe rigidity, or ratcheted, known as cogwheel rigidity.[22][36][41][42] The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity.[43] Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease.[36] 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.[44] 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,[45] and secondarily to bone fractures, loss of confidence, and reduced mobility.[46] Instability is absent in the initial stages, especially in younger people, especially before the development of bilateral symptoms.[47] 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.[36]

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.[48]

PD causes neuropsychiatric disturbances ranging from mild to severe including disorders of cognition, mood, behavior, and thought.[36] Cognitive disturbances can occur in the early stages or before diagnosis, and increase in prevalence with duration of the disease.[36][49] 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.[49][50] Other cognitive difficulties include slowed cognitive processing speed, impaired recall, and impaired perception and estimation of time.[49][50] Nevertheless, improvement appears when recall is aided by cues.[49] 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.[49][50]

A person with PD has two to six times the risk of dementia compared with the general population.[36][49] Up to 78% of people with PD have Parkinson's disease dementia.[51] The prevalence of dementia increases with age, and to a lesser degree, duration of the disease.[52] 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.[49]

Psychosis can be considered a symptom with a prevalence at its widest range from 26 to 83%.[13][53] 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.[54][55]

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.[36] 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.[13][56] Suicidal ideation is higher than in the general population, but suicidal attempts themselves are lower.[13][56] Risk factors for depression include disease onset under age 50, being female, previous history of depression, or severe motor symptoms.[13]

Anxiety has been estimated to have a prevalence in PD-affected people usually around 30–40% and up to 60% has been found.[13][56] Anxiety with PD is complex and consists of symptoms specific to PD.[57] 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.[57] 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.[13][58] 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.[13][58] Risk factors for anxiety in PD are disease onset under age 50, women, and off periods.[13] No standard treatment for PD-associated anxiety exists.[57]

Apathy and anhedonia can be defined as a loss of motivation and an impaired ability to experience pleasure[59] 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.[13] Apathy is associated with deficits in cognitive functions including executive and verbal memory.[56] Anhedonia occurs in 5–75% of people with PD, depending on the study population assessed and overlap with apathy.[60]

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.[61]

Punding, complicated, repetitive, aimless, stereotyped behaviors, is another side effect of anti-Parkinson medication.

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.[23][62] Other upper gastrointestinal symptoms include swallowing impairment (Oropharyngeal dysphagia) and small intestinal bacterial overgrowth.[63]

Individuals with Parkinson's have alpha-synuclein deposits in the digestive tract as well as the brain.[63] Constipation is one of the symptoms associated with an increased risk of PD and may precede diagnosis of PD.[63]

Sleep disorders occur with PD and can be worsened by medications.[36] Symptoms can manifest as daytime drowsiness (including sudden sleep attacks resembling narcolepsy), disturbances in Rapid eye movement sleep, or insomnia.[36] REM behavior disorder may begin years before the development of motor or cognitive elements of PD or dementia with Lewy bodies.[64]

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.[36]

Changes in perception may include an impaired sense of smell, disturbed vision, pain, and paresthesia (tingling and numbness).[36] These symptoms can occur years before diagnosis of the disease.[36]

Parkin crystal structure

Research indicates that PD results from a complex interaction between genetic and environmental factors.[7] Around 15% of diagnosed individuals have a first-degree relative who has the disease,[22] and 5–10% have a mutation in genes.[69][70] 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.[69] 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.[71][70] An autosomal dominant form has been associated with mutations in the LRP10 gene.[15][72]

About 5% of people with PD have mutations in the GBA1 gene.[73] These mutations are present in fewer than 1% of the unaffected population. The risk of developing PD is increased 20–30-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.[69] Alpha-synuclein activates ataxia telangiectasia mutated, a major DNA damage-repair signaling kinase.[74] 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.[74]

Mutations in some genes, including SNCA, LRRK2, and GBA, have been found to be risk factors for sporadic (nonfamilial) PD.[69] 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.[75][69] A mutation in GBA presents the greatest genetic risk of developing Parkinsons disease.[76]

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.[77]

Exposure to pesticides and head injury have each been linked with PD, but the risks are low. Not drinking caffeinated beverages is associated with small increases in risk.[61] Some toxins can cause parkinsonism, including manganese and carbon disulfide.[78][79][80][81]

Medical drugs are implicated in parkinsonism. Drug-induced parkinsonism is normally reversible by stopping the offending agent,[79] such as phenothiazines (chlorpromazine, promazine, etc.); butyrophenones (haloperidol, benperidol, etc.); 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.[79][82][83] Low concentrations of urate in the blood are associated with an increased risk.[84]

Other identifiable causes include infections and metabolic derangement. Neurodegenerative disorders may present with parkinsonism, and are also referred to as atypical parkinsonism or parkinson plus syndromes (illnesses with parkinsonism plus some other symptoms distinguishing them from PD) including multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies.[22][85] Dementia with Lewy bodies is another synucleinopathy and it has close pathological similarities with PD, especially with the subset of PD with dementia known as Parkinson's disease dementia. The relationship between PD and DLB is complex and incompletely understood.[86] It represents a continuum with variable distinguishing clinical and pathological attributes, or it may prove to be separate diseases.[86] 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.[87] 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.[88]

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.[89][79][90]

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.[75][95] These bodies first appear in the olfactory bulb, medulla oblongata and pontine tegmentum; individuals at this stage may be asymptomatic or have early nonmotor 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.[75] These brain sites are the main places of neuronal degeneration in PD, but Lewy bodies may be protective from cell death (with the abnormal protein sequestered or walled off). Other forms of alpha-synuclein (e.g. oligomers) that are not aggregated into Lewy bodies and Lewy neurites, may in fact be the toxic forms of the protein.[96][95] 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.[92]

Other mechanisms include proteasomal and lysosomal systems dysfunction and reduced mitochondrial activity.[96] 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 obscure.[97]

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.[98] 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.[99] 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.[100] 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.[101] 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.[102][103] 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.[102][103] Alpha-synuclein is produced in the gut and may migrate via the vagus nerve to the brainstem, and then to the substantia nigra.[104] Furthermore, the bacteria Proteus mirabilis has been associated with higher levels of alpha-synuclein and an increase of motor symptoms in PD patients.[105] Further elucidation of the causal role of alpha-synuclein, the role of inflammation, the gut-brain axis, as well as an understanding of the individual differences in immune stress responses is needed to better understand the pathological development of PD.

Computed tomography (CT) scans of people with PD usually appear normal.[111] 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.[112] In a meta-analysis, absence of this pattern was highly sensitive and specific for the disease.[113] A meta-analysis found that neuromelanin-MRI can discriminate individuals with Parkinson's from healthy subjects.[114] Diffusion MRI has shown potential in distinguishing between PD and Parkinson-plus syndromes, as well as between PD motor subtypes,[115] though its diagnostic value is still under investigation.[111] 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.[111]

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.[116] 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.[111] In the United States, DaTSCANs are only FDA approved to distinguish PD or Parkinsonian syndromes from essential tremor.[117]

Iodine-123-meta-iodobenzylguanidine myocardial scintigraphy can help locate denervation of the muscles of the heart which can support a PD diagnosis.[19]

Secondary parkinsonism – The multiple causes of parkinsonism can be differentiated through careful history, physical examination, and appropriate imaging.[79][19][118] This topic is further discussed in the causes section here.

Hot Cross Bun sign that is commonly found in MRI of multiple system atrophy

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.[119][118] Some key symptoms:[79][118]

• 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.[118][79]
• 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 and different postural difficulties

Other conditions that can have similar presentations to PD include:[120][79]

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.[126][132] 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 dopamine. A precursor of dopamine, levodopa, can pass through to 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.[133] 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.[134]

Prolonged use of levodopa is associated with the development of complications, such as involuntary movements (dyskinesias) and fluctuations in the impact of the medication.[126] 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).[126][135]^: 1989 Using lower doses of levodopa may reduce the risk and severity of these levodopa-induced complications.[136] A former strategy, called "drug holidays", to reduce levodopa-related dyskinesia and fluctuations was to withdraw levodopa medication for some time[132] which can bring on dangerous side effects such as neuroleptic malignant syndrome and is discouraged.[126] Most people with PD eventually need levodopa and later develop levodopa-induced fluctuations and dyskinesias.[126] 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.[137][138][139]

COMT metabolizes levodopa to 3-O-methyldopa. COMT inhibitors help stop this reaction, allowing for more levodopa to cross the blood–brain barrier and become dopamine where it is needed.[140]

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.[19] 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.[141] They are normally used in the management of later symptoms, but can be used in conjunction with levodopa/carbidopa when a person is experiencing the wearing off-phenomenon with their motor symptoms.[19][132]

Three COMT inhibitors are used to treat adults with PD and end-of-dose motor fluctuations – opicapone, entacapone, and tolcapone.[19] Tolcapone has been available for but its usefulness is limited by possible liver damage complications requiring liver-function monitoring.[142][79][19][141] Entacapone and opicapone cause little alteration to liver function.[141][143][144] Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.[145][79][146] Opicapone is a once-daily COMT inhibitor.[147][19]

Dopamine agonists that bind to dopamine receptors in the brain have similar effects to levodopa.[126] 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.[126][148] 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.[22] 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.[22] Thus, dopamine agonists are the preferred initial treatment for younger-onset PD, and levodopa is preferred for older-onset PD.[22]

Dopamine agonists produce side effects, including drowsiness, hallucinations, insomnia, nausea, and constipation.[126][132] Side effects appear with minimal clinically effective doses giving the physician reason to search for a different drug.[126] Agonists have been related to impulse-control disorders (such as increased sexual activity, eating, gambling, and shopping) more strongly than other antiparkinson medications.[149][132] They tend to be more expensive than levodopa.[22]

Apomorphine, a dopamine agonist, may be used to reduce off periods and dyskinesia in late PD.[126] It is administered only by intermittent injections or continuous subcutaneous infusions.[126] Secondary effects such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be closely monitored.[126] 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.[150] 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.[132]

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.[126] 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.[135]^: 1924[132] Selegiline has been shown to delay the need for beginning levodopa, suggesting that it might be neuroprotective and slow the progression of the disease.[151] An initial study indicated that selegiline in combination with levodopa increased the risk of death, but this has been refuted.[152]

Common side effects are nausea, dizziness, insomnia, sleepiness, and (in selegiline and rasagiline) orthostatic hypotension.[151][19] MAO-Bs are known to increase serotonin and cause a potentially dangerous condition known as serotonin syndrome.[151]

Other drugs such as amantadine may be useful as treatment of motor symptoms, but evidence for use is lacking.[126][153] Anticholinergics should not be used for dyskinesia or motor fluctuations but may be considered topically for drooling.[132] A diverse range of symptoms beyond those related to motor function can be treated pharmaceutically.[154] Examples are the use of quetiapine or clozapine for psychosis, cholinesterase inhibitors or memantine for dementia, and modafinil for excessive daytime sleepiness.[154][155][132] In 2016, pimavanserin was approved for the management of PD psychosis.[156] Doxepin and rasagline may reduce physical fatigue in PD.[157]

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 the discovery of levodopa has decreased the amount of procedures.[158] 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.[158] 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.[158] 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.[159] 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 dyskinesia.[158]

Four areas of the brain have been treated with neural stimulators in PD.[160] 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.[161]

Exercise programs are recommended in people with PD.[24] Some evidence shows that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality.[162][163] Regular physical exercise with or without physical therapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.[163] 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.[164] Clinical exercises may be an effective intervention targeting overall well-being of individuals with Parkinson's. Improvement in motor function and depression may happen.[165]

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.[166] 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).[167] 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.[168] 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.[169] Exercise may improve constipation.[23] If exercise reduces physical fatigue in PD remains unclear.[157]

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.[170]

The Lee Silverman voice treatment (LSVT) is one of the most widely practiced treatments for speech disorders associated with PD.[162][171] Speech therapy and specifically LSVT may improve speech.[162] 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.[162] 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.[162][172]

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.[173] As Parkinson's is uncurable, treatments focus on slowing decline and improving quality of life and are therefore palliative.[174]

Palliative care should be involved earlier, rather than later, in the disease course.[175][176] Palliative care specialists can help with physical symptoms, emotional factors such as loss of function and jobs, depression, fear, and existential concerns.[175][176][177]

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.[174] 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.[176][178]

Muscles and nerves that control the digestive process may be affected by PD, resulting in constipation and gastroparesis (prolonged emptying of stomach contents).[23] 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.[23] 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.[23]

Levodopa and proteins use the same transportation system in the intestine and the blood–brain barrier, thereby competing for access.[23] Taking them together results in reduced effectiveness of the drug.[23] 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.[23] To minimize interaction with proteins, levodopa should be taken 30 minutes before meals.[23] At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.[23]

Parkinson's awareness logo with red tulip symbol

The costs of PD to society are high, but methodological issues in research and differences between countries make precise calculations difficult.[193] The largest share of direct cost comes from inpatient care and nursing homes, while the share coming from medication is 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 Medicare program bears the largest share of medical costs, as most PD patients are over age 65. 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]

The birthday of James Parkinson, 11 April, has been designated as World Parkinson's Day.[27] 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 $115 million for research and nearly $50 million for education and advocacy 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]

Muhammad Ali at the World Economic Forum in Davos, at the age of 64. He had shown signs of parkinsonism from the age of 38 until his death.

Actor Michael J. Fox was 29 when diagnosed with PD,[201] and has used his diagnosis to increase awareness of the disease.[28] Fox embraced his Parkinson's in television roles, sometimes appearing without medication to further illustrate the effects of the condition. He has written four[202] autobiographies in which his fight against the disease plays a major role,[203] and appeared before the United States Congress without medication to illustrate the effects of the disease.[203] The Michael J. Fox Foundation aims to develop a cure for Parkinson's disease.[203] Fox received an honorary doctorate in medicine from Karolinska Institutet for his contributions to research in Parkinson's disease.[204]

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 PD research, focusing on quality of life for people with the disease.[29][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".[30] Whether he had PD or parkinsonism related to boxing is unresolved.[206][207]

At the time of his suicide in 2014, Robin Williams, the American actor and comedian, had been diagnosed with PD.[208] According to his widow, his autopsy found diffuse Lewy body disease,[208][209][210] while the autopsy used the term diffuse Lewy body dementia.[211] Dennis Dickson, a spokesperson for the Lewy Body Dementia Association, clarified the distinction by stating that diffuse Lewy body dementia is more commonly called diffuse Lewy body disease and refers to the underlying disease process.[211] Ian G. McKeith, professor and researcher of Lewy body dementias, commented that Williams' symptoms and autopsy findings were explained by dementia with Lewy bodies.[212]

Gene therapy typically involves the use of a noninfectious virus (i.e., a viral vector such as the adeno-associated viruses, a subset of small non developed viruses[218][219]) 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.[215] 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.[220]

A vaccine that primes the human immune system to destroy alpha-synuclein, PD01A (developed by Austrian company, Affiris), entered clinical trials and a phase one report in 2020 suggested safety and tolerability.[221][222] In 2018, an antibody, PRX002/RG7935, showed preliminary safety evidence in stage I trials supporting continuation to stage II trials.[223]

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.[96] 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.[224] An additional problem was the excess release of dopamine by the transplanted tissue resulting in dyskinesia.[224] In 2020, a first in human clinical trial reported the transplantation of induced pluripotent stem cells into the brain of a person with PD.[225]

Ventures have been undertaken to explore antagonists of adenosine receptors (specifically A_2A) as an avenue for novel drugs for Parkinson's.[226] Of these, istradefylline has emerged as the most successful medication and was approved for medical use in the United States in 2019.[227] It is approved as an add-on treatment to the levodopa/carbidopa regime.[227]