Motor

Four motor symptoms are considered as cardinal signs in PD: tremor, bradykinesia, rigidity, and postural instability, collectively known as parkinsonism.^[16] However, other motor-associated symptoms are common.

Tremor is the most common presenting sign and may appear at rest as well as during intentional movement with a frequency between 4–6 hertz (cycles per second).^[17] PD tremor tends to occur in the hands, but can affect other parts of the body, such as legs, arms, tongue, or lips, as well. It is often described as "pill-rolling", the tendency of the index finger and thumb to touch and perform a circular movement that reminds of the early pharmaceutical technique of manually making pills.^[18][19] Despite it being the most common sign, tremor is only present in about 70–90 percent of cases.^[18][20]

Bradykinesia is often considered the most important feature of Parkinson's disease^[21] and is also present in atypical parkinsonism. It describes difficulties in motor planning, beginning, and executing, resulting in overall slowed movement with reduced amplitude which affects sequential and simultaneous tasks.^[22] Hence, it interferes with daily activities such as dressing, feeding and bathing.^[21] Facial muscles involved in bradykinesia lead to characteristic reduced facial expression known as "masked face" or hypomimia.^[23]

Rigidity, also referred to as rigor or "stiffness", is the increased resistance during passive mobilization of a limb which is independent of movement direction nor velocity.^[24] It usually occurs after onset of tremor and bradykinesia on one or both sides of the body and can lead to muscle or joint pain as the disease progresses.^[25] As of 2024, it remains unclear whether rigidity is caused by a distinct biomechanical process or if it is the manifestation of another cardinal sign of PD.^[26]

Postural instability (PI) is typical in the later stages of the disease, leading to impaired balance and falls, and secondarily to bone fractures, thus, reduced mobility and quality of life. PI is absent in the initial stages and usually occurs 10–15 years after first diagnosis. Within the first three years after disease onset, PI may indicate atypical parkinsonism.^[27] While some sources may still refer to the cardinal signs as the classical triad out of tremor, bradykinesia and rigidity, PI is widely accepted as the fourth defining symptom, despite its unknown mechanism, thus forming a symptom tetrad.^[28] Together with bradykinesia and rigidity, it is responsable for the typical gait characterized by short shuffling steps and forward-flexed posture.^[29]

Other common motor signs include a slurred and quiet voice, or handwriting that progressively becomes smaller. Latter may occur prior to other typical symptoms, but the exact neurobiological mechanism, and therefore possible connections with other symptoms, remains unknown.^[30]

Neuropsychiatric

Neuropsychiatric symptoms (NPS) are common and range from mild disturbances to severe impairment, comprising abnormalities in cognition, mood, behavior, or thought which can interfere with daily activities, reduce quality of life, and increase the risk for admission to a nursing home. Some of them, such as depression and anxiety, are known to precede characteristic motor signs by up to several years and may herald the development of PD, while most of them worsen as the disease progresses.^[31] Research indicates, that patients with more severe motor symptoms are at higher risk for any NPS and that, conversely, NPS can worsen PD.^[32][33]

Depression is the most common NPS and occurs in nearly half of all patients. It features low mood and lack of pleasure and is more prevalent in females. The diagnosis can be challenging, since some symptoms of depression, such as psychomotor retardation, memory problems, or altered appetite, share similarities with psychiatric signs caused by PD.^[32] It may result in suicidal ideation which is more prevalent in PD. Nonetheless, suidical attempts themselves are lower than in general population.^[34]

Apathy is characterized by emotional indifference and arises in about 46 percent of cases. Diagnosis is difficult, as it may become indistinct from symptoms of depression.^[32][35]

Anxiety disorders (AD) develop in around 43 percent of cases.^[32] The most common are panic disorder, generalized anxiety disorder, and social anxiety disorder.^[31] Anxiety is known to cause deterioration in the symptoms of PD.^[33]

Parkinson's disease psychosis (PDP) is present in around 20 percent of cases^[36] and comprise hallucinations, illusions and delusions. It is associated with dopaminergic drugs used to treat the motor symptoms, higher morbidity, mortality a decrease in health-promoting behaviors and longer nursing home stays. Additionally, it correlates with depression and may herald onset of dementia in advanced stages. Unlike other psychotic forms, PDP typically presents with a clear sensorium. It might overlap with other psychiatric symptoms, making the diagnosis challenging.^[37]

Impulse-control disorders (ICD) can be seen in approximately 19 percent of all patients^[32] and, in the context of PD, are grouped along with compulsive behavior and dopamine dysregulation syndrome (DDS) within the broader spectrum of impulsive and compulsive behaviors (ICB). They are characterized by impulsivity and difficulty to control impulsive urges and are positively correlated with the use of dopamine agonists.^[38]

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.^[41][42] Other upper gastrointestinal symptoms include swallowing impairment (Oropharyngeal dysphagia) and small intestinal bacterial overgrowth.^[43]

Individuals with Parkinson's have alpha-synuclein deposits in the digestive tract as well as the brain.^[43] Constipation is one of the symptoms associated with an increased risk of PD and may precede diagnosis of PD.^[43]

Other

Sleep disorders occur with PD and can be worsened by medications.^[44] Symptoms can manifest as daytime drowsiness (including sudden sleep attacks resembling narcolepsy), disturbances in rapid eye movement sleep, or insomnia.^[44] REM behavior disorder may begin years before the development of motor or cognitive elements of PD or dementia with Lewy bodies.^[45]

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.^[44]

Changes in perception may include an impaired sense of smell, disturbed vision, pain, and paresthesia (tingling and numbness).^[44] These symptoms can occur years before diagnosis of the disease.^[44]

Genetic

Research indicates that PD results from a complex interaction between genetic and environmental factors.^[3][52] Around 15% of diagnosed individuals have a first-degree relative with the disease,^[53] and 5–10% have a mutation in at least one high risk gene.^[54][55] 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.^[54]

As of 2022, around 90 genetic risk loci have been identified.^[56][57] Many of these genes are known to contribute to cellular processes like cell death and inflammation, as well as the dysfunction of organelles like mitochondria, lysosomes, and endosomes.^[56] The greatest genetic risk factor for Parkinson's is a heterozygous mutation in the enzyme-encoding GBA1 gene. It is found in 5–10% of those with PD.^[58]: 2 A few genes are alone able to cause "monogenic" Parkinson's, which comprise 10 to 20 percent of cases.^[59]

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.^[54] Alpha-synuclein activates ataxia telangiectasia mutated, a major DNA damage-repair signaling kinase.^[60] 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.^[60] Major genetic risk factors that do not contribute to Lewy bodies include LRRK2 and PRKN.^[61]

Non-genetic

Although the vast majority or Parkinson's cases are believed to be non-genetic, identifying environmental risk factors and causality is extremely difficult due to the disease's often decade-long prodromal period.^[51]: 46 However, multi-decade studies have identified an increased likelihood of Parkinson's in association with agricultural work, pesticide exposure, and rural habitation.^[62] In particular, exposure to pesticides like paraquat, rotenone, benomyl, and mancozeb are associated with the onset of Parkinson's disease.^[63][64] The neurotoxic mechanisms for these pesticides have largely been identified: inhibition of the mitochondrial electron transport chain, increased oxidative stress, or inhibition of enzymes like aldehyde dehydrogenase and acetylcholinesterase.^[65] For most patients, consumption of pesticide-treated food products is believed to be the primary source of exposure.^[66]

Some medical drugs are implicated in parkinsonism; drug-induced parkinsonism is normally reversible by stopping the offending agent,^[67] such as phenothiazines, butyrophenones, metoclopramide, and Tetrabenazine. MPTP is a drug known for causing irreversible parkinsonism: consequently, it is commonly used in Parkinson's animal-model research.^[67][68][69] Low concentrations of urate in the blood are associated with an increased risk.^[70] Moreover, a possible link exists between PD and Helicobacter pylori infection that can prevent the absorption of some drugs, including levodopa.^[71][72]

Chlorinated solvents, used in commercial and industrial application like dry cleaning and degreasing, are associated with increased PD risk, particularly trichloroethylene.^[73][62] Other chemical risk factors include manganese, suspended particles from traffic fumes, and exposure to other heavy metals such as mercury and lead.^[62][74] Traumatic brain injuries (TBIs) are also strongly implicated as risk factors for PD.^[75] Additionally, although the underlying cause is unknown, melanoma is a widely-documented risk factor for PD.^[76]: 1260

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.^[77][83] 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.^[77] 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.^[84][83] 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.^{[80][page needed]}

Other mechanisms include proteasomal and lysosomal systems dysfunction and reduced mitochondrial activity.^[84] 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.^[85]

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.^[86] 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.^[87] 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.^[88]

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 Parkinson's disease, 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 people with PD. These monocytes can lead to more dopaminergic connection breakdown. In addition, monocytes isolated from people with Parkinson's disease express higher levels of the PD-associated protein, LRRK2, compared with non-PD individuals via vasodilation.^[89] 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 people with PD, that can lead to an increase in peripheral inflammation.^[90][91]

Peripheral inflammation can affect the gut-brain axis, an area of the body highly implicated in PD. People with PD have altered gut microbiota and colon problems years before motor issues arise.^[90][91] Alpha-synuclein is produced in the gut and may migrate via the vagus nerve to the brainstem, and then to the substantia nigra.^{[undue weight? – discuss][better source needed][92]}

Imaging

Computed tomography (CT) scans of people with PD usually appear normal.^[98] 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.^[99] In a meta-analysis, absence of this pattern was highly sensitive and specific for the disease.^[100] A meta-analysis found that neuromelanin-MRI can discriminate individuals with Parkinson's from healthy subjects.^[101] Diffusion MRI has shown potential in distinguishing between PD and Parkinson-plus syndromes, as well as between PD motor subtypes,^[102] though its diagnostic value is still under investigation.^[98] 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.^[98]

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.^[103] 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.^[98] In the United States, DaTSCANs are only FDA approved to distinguish PD or Parkinsonian syndromes from essential tremor.^[104]

Iodine-123-meta-iodobenzylguanidine myocardial scintigraphy can help locate denervation of the muscles of the heart which can support a PD diagnosis.^[81]

Differential diagnosis

Secondary parkinsonism – The multiple causes of parkinsonism can be differentiated through careful history, physical examination, and appropriate imaging.^[81][105] 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.^[106]

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.^[107] Presentation timelines and associated symptoms can help differentiate similar movement disorders from idiopathic Parkinson disease.^{[medical citation needed]}

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.^[108][109]

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.^[110][105] Some key symptoms:^[67][105]

• 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.^[105]
• 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:^[105][67]

Medications

This article needs to be updated. The reason given is: PMID 32171387. (October 2020)

Surgery

Treating motor symptoms with surgery was once a common practice but the discovery of levodopa has decreased the amount of procedures.^[150] 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.^[150] 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.^[150] 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.^[151] 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.^[150]

Four areas of the brain have been treated with neural stimulators in PD.^[152] 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.^[152]

Rehabilitation

Exercise programs are recommended in people with PD and recent reviews (2023) have demonstrated their efficacy.^[153][111] Some evidence shows that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality.^[154][155] Regular physical exercise with or without physical therapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.^[155] 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.^[156] Clinical exercises may be an effective intervention targeting overall well-being of individuals with Parkinson's. Improvement in motor function and depression may happen.^[157]

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.^[158] 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).^[159] 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.^[160] 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.^[161] Exercise may improve constipation.^[41] Whether exercise reduces physical fatigue in PD remains unclear.^[149]

Strength training exercise has been shown to increase manual dexterity in people with PD after exercising with manual putty. Improvements in both manual dexterity and strength can have a favorable impact on people with Parkinson's disease, fostering increased independence in daily activities that require grasping objects.^[162]

The Lee Silverman voice treatment (LSVT) is one of the most widely practiced treatments for speech disorders associated with PD.^[154][163] Speech therapy and specifically LSVT may improve speech.^[154] 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.^[154] 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.^[154][164]

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.^[165] As Parkinson's is uncurable, treatments focus on slowing decline and improving quality of life and are therefore palliative.^[166]

Palliative care should be involved earlier, rather than later, in the disease course.^[167][168] Palliative care specialists can help with physical symptoms, emotional factors such as loss of function and jobs, depression, fear, and existential concerns.^{[167][168][169]}

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.^[166] 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.^[168][170]

Muscles and nerves that control the digestive process may be affected by PD, resulting in constipation and gastroparesis (prolonged emptying of stomach contents).^[41] 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.^[41] 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.^[41]

Levodopa and proteins use the same transportation system in the intestine and the blood–brain barrier, thereby competing for access.^[41] Taking them together results in reduced effectiveness of the drug.^[41] 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.^[41] To minimize interaction with proteins, levodopa should be taken 30 minutes before meals.^[41] At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.^[41]

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.^[197] 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.^[198] 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.^[198]

Cost

Parts of this article (those related to this subsection) need to be updated. (August 2020)

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.^[199] Indirect costs are high, due to reduced productivity and the burden on caregivers.^[199] In addition to economic costs, PD reduces quality of life of those with the disease and their caregivers.^[199]

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.^[200]

Advocacy

The birthday of James Parkinson, 11 April, has been designated as World Parkinson's Day.^[188] 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.^[201]

Advocacy organizations include the National Parkinson Foundation, which has provided more than $180 million in care, research, and support services since 1982,^[202] 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;^[203][204] the American Parkinson Disease Association, founded in 1961;^[205] and the European Parkinson's Disease Association, founded in 1992.^[206]

Notable cases

In the 21st century, the diagnosis of Parkinson's among notable figures has increased the public's understanding of the disorder.^[207]

Actor Michael J. Fox was diagnosed with PD at 29 years old,^[208] and has used his diagnosis to increase awareness of the disease.^[209] To illustrate the effects of the disease, Fox has appeared without medication in television roles and before the United States Congress.^[210] The Michael J. Fox Foundation, which he founded in 2000, has raised over $2 billion for Parkinson's research.^[211] 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".^[212] Whether he had PD or parkinsonism related to boxing is unresolved.^[213][214] Cyclist and Olympic medalist Davis Phinney, diagnosed with Parkinson's at 40, started the Davis Phinney Foundation in 2004 to support PD research.^[215][216] Deng Xiaoping, former paramount leader of China, had advanced Parkinson's disease.^{[217][218][219]}

At the time of his suicide in 2014, Robin Williams, the American actor and comedian, had been diagnosed with PD,^[220] but his autopsy revealed dementia with Lewy bodies, highlighting difficulties in accurate diagnosis.^{[220][221][222][223][224]}

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.^[227] 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

In contrast to other neurodegenerative disorders, many Parkinson's symptoms can be attributed to the loss of a single cell type: mesencephalic dopaminergic (DA) neurons. Consequently, DA neuron regeneration is a promising therapeutic approach.^[234] Although most initial research sought to generate DA neuron precursor cells from fetal brain tissue,^[235] pluripotent stem cells—particularly induced pluripotent stem cells (iPSCs)—have become an increasingly popular tissue source.^[236][237]

Both fetal and iPSC-derived DA neurons have been transplanted into patients in clinical trials.^{[238][239]: 1926} Although some patients see improvements, the results are highly variable. Adverse effects, such as dyskinesia arising from excess dopamine release by the transplanted tissues, have also been observed.^[240][241]

Pharmaceutical

Antagonists of adenosine receptors (specifically A_2A) have been explored for Parkinson's.^[242] Of these, istradefylline has emerged as the most successful medication and was approved for medical use in the United States in 2019.^[243] It is approved as an add-on treatment to the levodopa/carbidopa regime.^[243] LRRK2 kinase inhibitors are also of interest.^[244]