Parkinson's disease

Four motor symptoms are considered cardinal in PD: tremor, slowness of movement (bradykinesia), rigidity, and postural instability.[31]

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.[31] It typically appears in only one hand, eventually affecting both hands as the disease progresses.[31] Frequency of PD tremor is between 4 and 6 hertz (cycles per second). A feature of tremor is pill-rolling, the tendency of the index finger and thumb to touch and perform together a circular movement.[31][32] The term derives from the similarity between the movement of people with PD and the early pharmaceutical technique of manually making pills.[32]

Bradykinesia (slowness of movement) is found in every case of PD, and is due to disturbances in motor planning of movement initiation, and associated with difficulties along the whole course of the movement process, from planning to initiation to execution of a movement. Performance of sequential and simultaneous movement is impaired. Bradykinesia is the most handicapping symptom of Parkinson’s disease leading to difficulties with everyday tasks such as dressing, feeding, and bathing. It leads to particular difficulty in carrying out two independent motor activities at the same time and can be made worse by emotional stress or concurrent illnesses. Paradoxically people with Parkinson's disease can often ride a bicycle or climb stairs more easily than walk on a level. While most physicians may readily notice bradykinesia, formal assessment requires a person to do repetitive movements with their fingers and feet.[33]

Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, an excessive and continuous contraction of muscles.[31] In parkinsonism, the rigidity can be uniform, known as "lead-pipe rigidity," or ratchety, known as "cogwheel rigidity."[16][31][34][35] The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity.[36] Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease.[31] In early stages of Parkinson's disease, rigidity is often asymmetrical and it tends to affect the neck and shoulder muscles prior to the muscles of the face and extremities.[37] 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,[38] and secondarily to bone fractures, loss of confidence, and reduced mobility.[39] Instability is often absent in the initial stages, especially in younger people, especially prior to the development of bilateral symptoms.[40] 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.[31]

Other recognized motor signs and symptoms include gait and posture disturbances such as festination (rapid shuffling steps and a forward-flexed posture when walking with no flexed arm swing). Freezing of gait (brief arrests when the feet seem to get stuck to the floor, especially on turning or changing direction), a slurred monotonous quiet voice, mask-like facial expression, and handwriting that gets smaller and smaller are other common signs.[41]

Parkinson's disease can cause neuropsychiatric disturbances, which can range from mild to severe. This includes disorders of cognition, mood, behavior, and thought.[31]

Cognitive disturbances can occur in the early stages of the disease and sometimes prior to diagnosis, and increase in prevalence with duration of the disease.[31][42] The most common cognitive deficit in PD is executive dysfunction, which can include problems with planning, cognitive flexibility, abstract thinking, rule acquisition, inhibiting inappropriate actions, initiating appropriate actions, working memory, and control of attention.[42][43] Other cognitive difficulties include slowed cognitive processing speed, impaired recall and impaired perception and estimation of time.[42][43] Nevertheless, improvement appears when recall is aided by cues.[42] Visuospatial difficulties are also part of the disease, seen for example when the individual is asked to perform tests of facial recognition and perception of the orientation of drawn lines.[42][43]

A person with PD has two to six times the risk of dementia compared to the general population.[31][42] Up to 78% of people with PD have Parkinson's disease dementia.[44] The prevalence of dementia increases with age and, to a lesser degree, duration of the disease.[45] 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.[42]

Impulse control disorders including pathological gambling, compulsive sexual behavior, binge eating, compulsive shopping and reckless generosity can be caused by medication, particularly orally active dopamine agonists. The dopamine dysregulation syndrome – with wanting of medication leading to overusage – is a rare complication of levodopa use.[46]

Punding in which complicated repetitive aimless stereotyped behaviors occur for many hours is another disturbance caused by anti-Parkinson medication.

Psychosis can be considered a symptom with a prevalence at its widest range from 26 to 83%.[10][47] Hallucinations or delusions occur in approximately 50% of people with PD over the course of the illness, and may herald the emergence of dementia. These range from minor hallucinations – "sense of passage" (something quickly passing beside the person) or "sense of presence" (the perception of something/someone standing just to the side or behind the person) – to full blown vivid, formed visual hallucinations and paranoid ideation. Auditory hallucinations are uncommon in PD, and are rarely described as voices. It is now believed that psychosis is an integral part of the disease. A psychosis with delusions and associated delirium is a recognized complication of anti-Parkinson drug treatment and may also be caused by urinary tract infections (as frequently occurs in the fragile elderly), but drugs and infection are not the only factors, and underlying brain pathology or changes in neurotransmitters or their receptors (e.g., acetylcholine, serotonin) are also thought to play a role in psychosis in PD.[48][49]

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.[31]

Depression has been estimated to appear in anywhere from 20 to 35% of people with PD, and can appear at any stage of the disease. In Parkinson's, depression can manifest with symptoms that are common to the disease process (fatigue, insomnia, and difficulty with concentration) which makes diagnosis difficult. The imbalance and change in dopamine, serotonin, and noradrenergic hormones are known to be a primary cause of depression in PD affected people.[10] Another cause is the functional impairment that is caused by the disease.[50] Symptoms of depression can include loss of interest, sadness, guilt, feelings of helplessness/hopelessness/guilt, and suicidal ideation. Suicidal ideation in PD affected people is higher than in the general population, but suicidal attempts themselves are lower than in people with depression without PD.[10][50] Risk factors for depression in PD can include disease onset under age 50, being a woman, previous history of depression, severe motor symptoms, and others.[10]

Anxiety has been estimated to have a prevalence in PD affected people around 30%-40% (however up to 60% has been found).[10][50] Anxiety can often be found during "off" periods (periods of time where medication is not working as well as it did before) with PD affected people suffering from panic attacks more frequently compared to the general population. Both anxiety and depression have been found to be associated with decreased quality of life.[10][51] Symptoms can range from mild and episodic to chronic with potential causes being abnormal gamma-aminobutyric acid levels as well as embarrassment or fear about their symptoms/disease.[10][51] Risk factors for anxiety in PD are disease onset under age 50, women, and "off" periods.[10]

Apathy and anhedonia can be defined as a loss of motivation and an impaired ability to experience pleasure, respectively. They are symptoms classically associated with depression however differ in PD affected people in treatment, mechanism, and doesn't always occur with depression. 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.[10] Apathy is associated with deficits in cognitive functions including executive and verbal memory.[50]

Sleep disorders are a feature of the disease and can be worsened by medications.[31] Symptoms can manifest as daytime drowsiness (including sudden sleep attacks resembling narcolepsy), disturbances in REM sleep, or insomnia.[31] REM behavior disorder (RBD), in which people act out dreams, sometimes injuring themselves or their bed partner, may begin many years before the development of motor or cognitive features of PD or DLB.[52]

Alterations in the autonomic nervous system can lead to orthostatic hypotension (low blood pressure upon standing), oily skin and excessive sweating, urinary incontinence, and altered sexual function.[31] Constipation and impaired stomach emptying (gastric dysmotility) can be severe enough to cause discomfort and even endanger health.[17] Changes in perception may include an impaired sense of smell, disturbed vision, pain, and paresthesia (tingling and numbness).[31] All of these symptoms can occur years before diagnosis of the disease.[31]

Exposure to pesticides and a history of head injury have each been linked with Parkinson disease (PD), but the risks are modest. Never having smoked cigarettes, and never drinking caffeinated beverages, are also associated with small increases in risk of developing PD.[46]

Low concentrations of urate in the blood serum is associated with an increased risk of PD.[57]

Different medical drugs have been indicated in cases of parkinsonism. Drug-induced parkinsonism is normally reversible by stopping the offending agent.[58] Drugs include but not are not limited to:

• Phenothiazines (chlorpromazine, promazine, etc.)
• Butyrophenones (haloperidol, benperidol, etc.)
• Metoclopramide
• 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.[58][59][60]

Some toxins can cause parkinsonism. These toxins include but are not limited to manganese and carbon disulfide [61][58][62][63]

Parkin crystal structure

Research indicates that PD is the product of a complex interaction of genetic and environmental factors.[4] Around 15% of individuals with PD have a first-degree relative who has the disease,[16] and 5–10% of people with PD are known to have forms of the disease that occur because of a mutation in one of several specific genes.[64][65] Harboring one of these gene mutations may not lead to the disease; susceptibility factors put the individual at an increased risk, often in combination with other risk factors, which also affect age of onset, severity and progression.[64] At least 11 autosomal dominant and 9 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, VPS35. Autosomal recessive genes include PRKN, PINK1, PARK7, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, and VPS13C. Some genes are x-linked or have unknown inheritance pattern: those include PARK10, PARK12, and PARK16. 22q11 deletion is also known to be associated with PD.[66][65] An autosomal dominant form has been associated with mutations in the LRP10 gene.[12][67]

About 5% of people with PD have mutations in the GBA1 gene.[68] These mutations are present in less 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 features, 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.

SNCA gene mutations are important in PD because the protein which this gene encodes, alpha-synuclein, is the main component of the Lewy bodies that accumulate in the brains of people with PD.[64] Alpha-synuclein activates ATM (ataxia telangiectasia mutated), a major DNA damage repair signaling kinase.[69] 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.[69]

Mutations in some genes, including SNCA, LRRK2 and GBA, have been found to be risk factors for "sporadic" (non-familial) PD.[64] Mutations in the gene LRRK2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases.[70][64] A mutation in GBA presents the greatest genetic risk of developing Parkinsons disease.[71]

Several Parkinson-related genes are involved in the function of lysosomes, organelles that digest cellular waste products. It has been suggested that some cases of PD may be caused by lysosomal disorders that reduce the ability of cells to break down alpha-synuclein.[72]

Vascular parkinsonism is the phenomena 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 are similar causes of both vascular parkinsonism and idiopathic Parkinson's Disease, so they can present with many of the same symptoms. Differentiation can be made with careful bedside examination, history taking, and imaging.[73][58][74]

Other identifiable causes of parkinsonism include infections and metabolic derangement. Several neurodegenerative disorders also may present with parkinsonism and are sometimes referred to as "atypical parkinsonism" or "Parkinson plus" syndromes (illnesses with parkinsonism plus some other features distinguishing them from PD). They include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies (DLB).[16][75] Dementia with Lewy bodies is another synucleinopathy and it has close pathological similarities with PD, especially with the subset of PD cases with dementia known as Parkinson's disease dementia. The relationship between PD and DLB is complex and incompletely understood.[76] They may represent parts of a continuum with variable distinguishing clinical and pathological features or they may prove to be separate diseases.[76]

There is speculation of several mechanisms by which the brain cells could be lost.[81] One mechanism consists of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. This insoluble protein accumulates inside neurons forming inclusions called Lewy bodies.[70][82] According to the Braak staging, a classification of the disease based on pathological findings proposed by Heiko Braak, Lewy bodies first appear in the olfactory bulb, medulla oblongata and pontine tegmentum; individuals at this stage may be asymptomatic or may have early non-motor symptoms (such as loss of sense of smell, or some sleep or automatic dysfunction). As the disease progresses, Lewy bodies develop in the substantia nigra, areas of the midbrain and basal forebrain and, finally, the neocortex.[70] These brain sites are the main places of neuronal degeneration in PD; however, Lewy bodies may not cause cell death and they may be protective (with the abnormal protein sequestered or walled off). Other forms of alpha-synuclein (e.g., oligomers) that are not aggregated in Lewy bodies and Lewy neurites may actually be the toxic forms of the protein.[81][82] In people with dementia, a generalized presence of Lewy bodies is common in cortical areas. Neurofibrillary tangles and senile plaques, characteristic of Alzheimer's disease, are not common unless the person is demented.[78]

Other cell-death mechanisms include proteasomal and lysosomal system dysfunction and reduced mitochondrial activity.[81] Iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. It may be related to oxidative stress, protein aggregation and neuronal death, but the mechanisms are not fully understood.[83]

Computed tomography (CT) scans of people with PD usually appear normal.[90] MRI has become more accurate in diagnosis of the disease over time, specifically through iron-sensitive T2* and SWI sequences at a magnetic field strength of at least 3T, both of which can demonstrate absence of the characteristic 'swallow tail' imaging pattern in the dorsolateral substantia nigra.[91] In a meta-analysis, absence of this pattern was highly sensitive and specific for the disease.[92] A 2020 meta-analysis found that neuromelanin-MRI had a favorable diagnostic performance in discriminating individuals with Parkinson's from healthy subjects.[93] Diffusion MRI has shown potential in distinguishing between PD and Parkinson-plus syndromes, though its diagnostic value is still under investigation.[90] CT and MRI are also used to rule out other diseases that can be secondary causes of parkinsonism, most commonly encephalitis and chronic ischemic insults, as well as less frequent entities such as basal ganglia tumors and hydrocephalus.[90]

The metabolic activity of dopamine transporters in the basal ganglia can be directly measured with PET and SPECT scans, with the DaTSCAN being a common proprietary version of this study. It has shown high agreement with clinical diagnoses of Parkinson's.[94] Reduced dopamine-related activity in the basal ganglia can help exclude drug-induced Parkinsonism. This finding is not entirely specific, however, and can be seen with both PD and Parkinson-plus disorders.[90] In the United States, DaTSCANs are only FDA approved to distinguish Parkinson’s disease or Parkinsonian syndromes from essential tremor.[95]

Iodine-123-meta-iodobenzylguanidine myocardial scintigraphy can help find denervation of the nerves around the heart, which can support a PD diagnosis.[14]

Secondary Parkinsonism - There can be multiple causes of Parkinsonism including drugs, toxins, and vascular incidents (such as strokes). These can be differentiated between with careful history, physical, and appropriate imaging.[58][14][96] This topic is further discussed in the causes section here.

"Hot Cross Bun" sign that is commonly found in MRI of Mutliple 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 (especially focused on onset of specific symptoms), progression of the disease, and response to treatment.[97][96] Some key features between them:[58][96]

• Corticobasal syndrome - levodopa-resistance, myoclonus, dystonia, corticosensory loss, apraxia, and non-fluent aphasia.
• 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.
• Dementia with Lewy bodies - levodopa resistance, cognitive predominance before motor symptoms, and fluctuating congnitive symptoms. Visual hallucinations are very common in this disease however PD patients can also have those.

Essential tremor - Essential tremor can at first look like parkinsonsim, however there are key differentiators. In essential tremor the tremor will get worse with action (where in PD it gets better), there will be a lack of other symptoms common in PD, and normal DatSCAN.[96][58]

Other conditions that can have similar presentations to PD include:[98][58]

The motor symptoms of PD are the result of reduced dopamine production in the brain's basal ganglia. Dopamine does not cross the blood-brain barrier, so it cannot be taken as a medicine to boost the brain's depleted levels of dopamine. However a precursor of dopamine, levodopa, can pass through to the brain where it is readily converted to dopamine, and administration of levodopa temporarily diminishes the motor symptoms of PD. Levodopa has been the most widely used PD treatment for over 40 years.[105]

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.[109] Carbidopa and benserazide are dopa decarboxylase inhibitors which do not cross the blood-brain barrier and inhibit the conversion of levodopa to dopamine outside the brain, reducing side effects and improving the availability of levodopa for passage into the brain. One of these drugs is usually taken along with levodopa, often combined with levodopa in the same pill.[110]

Levodopa-use leads in the long term to the development of complications: involuntary movements called dyskinesias, and fluctuations in the effectiveness of the medication.[105] When fluctuations occur, a person can cycle through phases with good response to medication and reduced PD symptoms ("on" state), and phases with poor response to medication and significant PD symptoms ("off" state).[105] Using lower doses of levodopa may reduce the risk and severity of these levodopa-induced complications.[111] A former strategy to reduce levodopa-related dyskinesia and fluctuations was to withdraw levodopa medication for some time. This is now discouraged since it can bring on dangerous side effects such as neuroleptic malignant syndrome.[105] Most people with PD will eventually need levodopa and will later develop levodopa-induced fluctuations and dyskinesias.[105]

There are controlled-release versions of levodopa. Older controlled-release levodopa preparations have poor and unreliable absorption and bioavailability and have not demonstrated improved control of PD motor symptoms or a reduction in levodopa-related complications when compared to immediate release preparations. A newer extended-release levodopa preparation does seem to be more effective in reducing fluctuation,s but in many people problems persist. Intestinal infusions of levodopa (Duodopa) can result in striking improvements in fluctuations compared to oral levodopa when the fluctuations are due to insufficient uptake caused by gastroparesis. Other oral, longer acting formulations are under study and other modes of delivery (inhaled, transdermal) are being developed.[110]

COMT metabolize 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.[112]

During the course of Parkinson's disease, affected people can experience what's known as a "wearing off phenomena" where they have a recurrence of symptoms after a dose of levodopa but right before their next dose.[14] Catechol-O-methyltransferase (COMT), is a protein that degrades levodopa before it can cross the blood-brain barrier and these inhibitors allow for more levodopa to cross.[113] They are normally not used in the management of early symptoms however can be used in conjunction with levodopa/carbidopa when a person is experiencing the "wearing off phenomena" with their motor symptoms.[14]

There are three COMT inhibitors available to treat adults with Parkinson’s Disease and end-of-dose motor fluctuations: opicapone, entacapone and tolcapone.[14] Tolcapone has been available for several years however its usefulness is limited by possible liver damage complications and therefore requires liver function monitoring.[114][58][14][113] Entacapone and opicapone have not been shown to cause significant alterations to liver function.[113][115][116] Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.[117][58][118] Opicapone is a once-daily COMT inhibitor.[119][14]

Several dopamine agonists that bind to dopamine receptors in the brain have similar effects to levodopa.[105] These were initially used as a complementary therapy to levodopa for individuals experiencing levodopa complications (on-off fluctuations and dyskinesias); they are now mainly used on their own as first therapy for the motor symptoms of PD with the aim of delaying the initiation of levodopa therapy and so delaying the onset of levodopa's complications.[105][120] Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride.

Though dopamine agonists are less effective than levodopa at controlling PD motor symptoms, they are usually effective enough to manage these symptoms in the first years of treatment.[16] 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.[16] Thus dopamine agonists are the preferred initial treatment for younger onset PD, and levodopa is preferred for older onset PD.[16]

Dopamine agonists produce significant, although usually mild, side effects including drowsiness, hallucinations, insomnia, nausea, and constipation.[105] Sometimes side effects appear even at a minimal clinically effective dose, leading the physician to search for a different drug.[105] Agonists have been related to impulse control disorders (such as compulsive sexual activity, eating, gambling and shopping) even more strongly than levodopa.[121] They tend to be more expensive than levodopa.[16]

Apomorphine, a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD.[105] It is administered by intermittent injections or continuous subcutaneous infusions.[105] Since secondary effects such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be closely monitored.[105] Two dopamine agonists that are administered through skin patches (lisuride and rotigotine) and are useful for people in the initial stages and possibly to control off states in those in the advanced state.[122]

MAO-B inhibitors (safinamide, selegiline and rasagiline) increase the amount of dopamine in the basal ganglia by inhibiting the activity of monoamine oxidase B (MAO-B), an enzyme which breaks down dopamine.[105] They have been found to help alleviate motor symptoms when used as monotherapy (on their own) and, when used in conjunction with levodopa, reduce the time spent in the "off" phase. Selegiline has been shown to delay the need for levodopa commencement, suggesting that it might be neuroprotective and slow the progression of the disease (however this has not been proven).[123] An initial study indicated that selegiline in combination with levodopa increased the risk of death, but this has been refuted.[124]

Common side-effects are nausea, dizziness, insomnia, sleepiness, and (in selegiline and rasagiline) orthostatic hypotension.[123][14] Along with dopamine, MAO-Bs are known to increase serotonin, so care must be used when used with certain antidepressants due to a potentially dangerous condition known as serotonin syndrome.[123]

Other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms. However, the evidence supporting them lacks quality, so they are not first choice treatments.[105][125] In addition to motor symptoms, PD is accompanied by a diverse range of symptoms. A number of drugs have been used to treat some of these problems.[126] Examples are the use of quetiapine for psychosis, cholinesterase inhibitors for dementia, and modafinil for daytime sleepiness.[126][127] In 2016 pimavanserin was approved for the management of Parkinson's disease psychosis.[128]

Doxepin and rasagline may reduce physical fatigue in PD.[129]

Placement of an electrode into the brain. The head is stabilised in a frame for stereotactic surgery.

Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa, the number of operations has declined.[130] Studies in the past few decades have led to great improvements in surgical techniques, so that surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient.[130] Surgery for PD can be divided in two main groups: lesional and deep brain stimulation (DBS). Target areas for DBS or lesions include the thalamus, the globus pallidus or the subthalamic nucleus.[130] Deep brain stimulation is the most commonly used surgical treatment, developed in the 1980s by Alim Louis Benabid and others. It involves the implantation of a medical device called a neurostimulator, which sends electrical impulses to specific parts of the brain. DBS is recommended for people who have PD with motor fluctuations and tremor inadequately controlled by medication, or to those who are intolerant to medication, as long as they do not have severe neuropsychiatric problems.[131] 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.[130]

Four areas of the brain have been treated with neural stimulators in PD.[132] These are the globus pallidus interna, thalamus, subthalamic nucleus and the pedunculopontine nucleus. DBS of the globus pallidus interna improves motor function while DBS of the thalamic DBS improves tremor but has little effect 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 reduction in medication. Pedunculopontine nucleus DBS remains experimental at present. Generally DBS is associated with 30–60% improvement in motor score evaluations.

Exercise programs are recommended in people with Parkinson's disease.[18] There is some evidence that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality.[133][134] Regular physical exercise with or without physical therapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.[134] When an exercise program is performed under the supervision of a physiotherapist, there are more improvements in motor symptoms, mental and emotional functions, daily living activities, and quality of life compared to a self-supervised exercise program at home.[135] In terms of improving flexibility and range of motion for people experiencing rigidity, generalized relaxation techniques such as gentle rocking have been found to decrease excessive muscle tension. Other effective techniques to promote relaxation include slow rotational movements of the extremities and trunk, rhythmic initiation, diaphragmatic breathing, and meditation techniques.[136] As for gait and addressing the challenges associated with the disease such as hypokinesia (slowness of movement), shuffling and decreased arm swing; physiotherapists have a variety of strategies to improve functional mobility and safety. Areas of interest with respect to gait during rehabilitation programs focus on, but are not limited to improving gait speed, the base of support, stride length, trunk and arm swing movement. Strategies include utilizing assistive equipment (pole walking and treadmill walking), verbal cueing (manual, visual and auditory), exercises (marching and PNF patterns) and altering environments (surfaces, inputs, open vs. closed).[137] Strengthening exercises have shown improvements in strength and motor function for people with primary muscular weakness and weakness related to inactivity with mild to moderate Parkinson's disease. However, reports show a significant interaction between strength and the time the medications was taken. Therefore, it is recommended that people with PD should perform exercises 45 minutes to one hour after medications when they are at their best.[138] Also, due to the forward flexed posture, and respiratory dysfunctions in advanced Parkinson's disease, deep diaphragmatic breathing exercises are beneficial in improving chest wall mobility and vital capacity.[139] Exercise may improve constipation.[17] It is unclear if exercise reduces physical fatigue in PD.[129]

One of the most widely practiced treatments for speech disorders associated with Parkinson's disease is the Lee Silverman voice treatment (LSVT).[133][140] Speech therapy and specifically LSVT may improve speech.[133] Occupational therapy (OT) aims to promote health and quality of life by helping people with the disease to participate in as many of their daily living activities as possible.[133] There have been few studies on the effectiveness of OT and their quality is poor, although there is some indication that it may improve motor skills and quality of life for the duration of the therapy.[133][141]

Palliative care is specialized medical care for people with serious illnesses, including Parkinson's. The goal of this speciality is to improve quality of life for both the person with Parkinson's and the family by providing relief from the symptoms, pain, and stress of illnesses.[142] As Parkinson's is not a curable disease, all treatments are focused on slowing decline and improving quality of life, and are therefore palliative in nature.[143]

Palliative care should be involved earlier, rather than later in the disease course.[144][145] Palliative care specialists can help with physical symptoms, emotional factors such as loss of function and jobs, depression, fear, and existential concerns.[144][145][146]

Along with offering emotional support to both the affected person and family, palliative care serves an important role in addressing goals of care. People with Parkinson's may have many difficult decisions to make as the disease progresses such as wishes for feeding tube, non-invasive ventilator, and tracheostomy; wishes for or against cardiopulmonary resuscitation; and when to use hospice care.[143] Palliative care team members can help answer questions and guide people with Parkinson's on these complex and emotional topics to help them make the best decision based on their own values.[145][147]

Muscles and nerves that control the digestive process may be affected by PD, resulting in constipation and gastroparesis (food remaining in the stomach for a longer period than normal).[17] A balanced diet, based on periodical nutritional assessments, is recommended and should be designed to avoid weight loss or gain and minimize consequences of gastrointestinal dysfunction.[17] As the disease advances, swallowing difficulties (dysphagia) may appear. In such cases it may be helpful to use thickening agents for liquid intake and an upright posture when eating, both measures reducing the risk of choking. Gastrostomy to deliver food directly into the stomach is possible in severe cases.[17]

Levodopa and proteins use the same transportation system in the intestine and the blood–brain barrier, thereby competing for access.[17] When they are taken together, this results in a reduced effectiveness of the drug.[17] Therefore, when levodopa is introduced, excessive protein consumption is discouraged and well balanced Mediterranean diet is recommended. In advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons.[17] To minimize interaction with proteins, levodopa should be taken 30 minutes before meals.[17] At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.[17]

"Parkinson's awareness" logo with red tulip symbol

The costs of PD to society are high, but precise calculations are difficult due to methodological issues in research and differences between countries.[160] The annual cost in the UK is estimated to be between £49 million and £3.3 billion, while the cost per affected person per year in the U.S. is probably around $10,000 and the total burden around $23 billion.[160] The largest share of direct cost comes from inpatient care and nursing homes, while the share coming from medication is substantially lower.[160] Indirect costs are high, due to reduced productivity and the burden on caregivers.[160] In addition to economic costs, PD reduces quality of life of those with the disease and their caregivers.[160]

The birthday of James Parkinson, 11 April, has been designated as World Parkinson's Day.[21] 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.[161] Advocacy organizations include the National Parkinson Foundation, which has provided more than $180 million in care, research and support services since 1982,[162] 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;[163][164] the American Parkinson Disease Association, founded in 1961;[165] and the European Parkinson's Disease Association, founded in 1992.[166]

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 has PD and has greatly increased the public awareness of the disease.[22] After diagnosis, Fox embraced his Parkinson's in television roles, sometimes acting without medication, in order to further illustrate the effects of the condition. He has written two autobiographies in which his fight against the disease plays a major role,[167] and appeared before the United States Congress without medication to illustrate the effects of the disease.[167] The Michael J. Fox Foundation aims to develop a cure for Parkinson's disease.[167] Fox received an honorary doctorate in medicine from Karolinska Institutet for his contributions to research in Parkinson's disease.[168]

Professional cyclist and Olympic medalist Davis Phinney, who was diagnosed with young onset Parkinson's at age 40, started the Davis Phinney Foundation in 2004 to support Parkinson's research, focusing on quality of life for people with the disease.[23][169]

Boxer Muhammad Ali showed signs of Parkinson's when he was 38, but was not diagnosed until he was 42, and has been called the "World's most famous Parkinson's patient".[24] Whether he had PD or parkinsonism related to boxing is unresolved.[170][171]

PD is not known to occur naturally in any species other than humans, although animal models which show some features of the disease are used in research. The appearance of parkinsonism in a group of drug addicts in the early 1980s who consumed a contaminated batch of the synthetic opiate MPPP led to the discovery of the chemical MPTP as an agent that causes parkinsonism in non-human primates as well as in humans.[173] Other predominant toxin-based models employ the insecticide rotenone, the herbicide paraquat and the fungicide maneb.[174] Models based on toxins are most commonly used in primates. Transgenic rodent models that replicate various aspects of PD have been developed.[175] The use of neurotoxin 6-hydroxydopamine, creates a model of Parkinson's disease in rats by targeting and destroying dopaminergic neurons in the nigrostriatal pathway when injected into the substantia nigra.[176]

Gene therapy typically involves the use of a non-infectious virus (i.e., a viral vector such as the adeno-associated virus) to shuttle genetic material into a part of the brain. Several approaches have been tried. These approaches have involved the expression of growth factors to try 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). There have been no reported safety concerns, but the approaches have largely failed in phase 2 clinical trials.[172] The delivery of GAD showed promise in phase 2 trials in 2011, but whilst effective at improving motor function was inferior to DBS. Follow-up studies in the same cohort have suggested persistent improvement.[177]

Several chemical compounds, such as GDNF (chemical structure pictured) have been proposed as neuroprotectors in PD, but their effectiveness has not been proven.

Investigations on neuroprotection are at the forefront of PD research. Several molecules have been proposed as potential treatments.[81] However, none of them have been conclusively demonstrated to reduce degeneration.[81] Agents currently under investigation include, antiglutamatergics, monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrials (coenzyme Q10, creatine), calcium channel blockers (isradipine) and growth factors (GDNF).[81] Reducing alpha-synuclein pathology is a major focus of preclinical research.[178] A vaccine that primes the human immune system to destroy alpha-synuclein, PD01A (developed by Austrian company, Affiris), entered clinical trials and a phase 1 report in 2020 suggested safety and tolerability.[179][180] In 2018, an antibody, PRX002/RG7935, showed preliminary safety evidence in stage I trials supporting continuation to stage II trials.[181]

Since early in the 1980s, fetal, porcine, carotid or retinal tissues have been used in cell transplants, in which dissociated cells are injected into the substantia nigra in the hope that they will incorporate themselves into the brain in a way that replaces the dopamine-producing cells that have been lost.[81] 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. There was initial evidence of mesencephalic dopamine-producing cell transplants being beneficial, double-blind trials to date have not determined whether there is a long-term benefit.[182] An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dyskinesia.[182] In 2020, a first in human clinical trial reported the transplantation of induced pluripotent stem cells into the brain of a person suffering from Parkinson's disease.[183]

Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias.[184] Its usefulness in PD is an open research topic.[185] Several nutrients have been proposed as possible treatments; however there is no evidence that vitamins or food additives improve symptoms.[186] There is no evidence to substantiate that acupuncture and practice of Qigong, or T'ai chi, have any effect on the course of the disease or symptoms.[187][188][189]

The role of the gut–brain axis and the gut flora in Parkinsons became a topic of study in the 2010s, starting with work in germ-free transgenic mice, in which fecal transplants from people with PD had worse outcomes. Some studies in humans have shown a correlation between patterns of dysbiosis in the gut flora in the people with PD, and these patterns, along with a measure of severity of constipation, could diagnose PD with a 90% specificity but only a 67% sensitivity. As of 2017 some scientists hypothesized that changes in the gut flora might be an early site of PD pathology, or might be part of the pathology.[190][191] Evidence indicates that gut microbiota can produce lipopolysaccharide that interferes with the normal function of α-synuclein.[192]

Ventures have been undertaken to explore antagonists of adenosine receptors (specifically A_2A) as an avenue for novel drugs for Parkinson's.[193] Of these, istradefylline has emerged as the most successful medication and was approved for medical use in the United States in 2019.[194] It is approved as an add-on treatment to the levodopa/carbidopa regime.[194]