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{{Short description|Progressive neurodegenerative disease}}
{{Redirect|Parkinson's|the medical journal|Parkinson's Disease (journal)|other uses}}
{{Cs1 config|name-list-style=vanc|display-authors=6}}
{{Use dmy dates|date=July 2024}}
{{Infobox medical condition
| name = Parkinson's disease
| synonyms = {{hlist|Idiopathic or primary parkinsonism|hypokinetic rigid syndrome|paralysis agitans|shaking palsy}}
| image = {{Multiple image|perrow = 2|total_width=300|align=center|image_gap=10
| border = infobox
| image_style = border:none;
| image1 = Parkinson’s disease 1880s.jpg
| caption1 = A. 1880s illustration of Parkinson's disease (PD)
| image2 = Mild motor-predominant PD.jpg
| caption2 = B. Mild motor-predominant PD
| image3 = Intermediate PD.jpg
| caption3 = C. Intermediate PD
| image4 = Diffuse malignant PD.jpg
| caption4 = D. Diffuse malignant PD
| footer =
}}
| symptoms = {{hlist|[[Tremor]]|[[bradykinesia]]|[[spasticity|rigidity]]|[[postural instability]]|[[dysautonomia]]|[[Depression (mood)|depression]]|[[anxiety]]|[[sleep disorder|sleep abnormalities]]}}
| complications = {{hlist|[[Falls in older adults|Falls]]|[[Parkinson's disease dementia|dementia]]|[[aspiration pneumonia]]}}
| onset = Age over 60{{sfn|National Institute of Neurological Disorders and Stroke}}
| duration = Long-term
| risks = {{hlist|Family history|[[dyspepsia]]|[[general anesthesia]]|[[pesticide|pesticide exposure]]|[[head injuries]]}}
| diagnosis = {{hlist|History and neurologic examination|[[medical imaging]]|dopamine levels in urine}}
| differential = {{hlist|[[Dementia with Lewy bodies]]|[[progressive supranuclear palsy]]|[[essential tremor]]|[[antipsychotic]] use {{Sfn|Ferri|2010|loc= Chapter P}}|[[fragile X-associated tremor/ataxia syndrome]]|[[Huntington's disease]]|[[dopamine-responsive dystonia]]|[[Wilson's disease]]}} {{sfn|Koh|Ito|2017}}
| treatment = Supportive measures & control of symptoms, [[physical therapy]], [[deep brain stimulation]], medication
| medication = [[Levodopa]], [[COMT inhibitor]]s, [[Aromatic L-amino acid decarboxylase inhibitor|AAAD inhibitors]], [[dopamine agonist]]s, [[MAO-B inhibitor]]s
| prognosis = No known cure; near-normal life expectancy.
| named after = [[James Parkinson]]
}}
'''Parkinson's disease''' ('''PD'''), or simply '''Parkinson's''', is a [[neurodegenerative disease]] primarily of the [[central nervous system]], affecting both [[motor system|motor]] and non-motor systems. Symptoms typically develop gradually and non-motor issues become more prevalent as the disease progresses. The motor symptoms are collectively called [[parkinsonism]] and include [[tremor]]s, [[bradykinesia]], [[spasticity|rigidity]], and [[postural instability]] (i.e., difficulty maintaining balance). Non-motor symptoms develop later in the disease and include [[behavior change (individual)|behavioral changes]] or [[mental disorder|neuropsychiatric problems]], such as [[sleep abnormalities]], [[psychosis]], [[anosmia]], and [[mood swing]]s.
Most Parkinson's disease cases are [[idiopathic disease|idiopathic]], though contributing factors have been identified. Pathophysiology involves progressive [[nerve cell death|degeneration of nerve cells]] in the [[substantia nigra]], a [[midbrain]] region that provides [[dopamine]] to the [[basal ganglia]], a system involved in voluntary [[motor control]]. The cause of this cell death is poorly understood, but involves the aggregation of [[alpha-synuclein]] into [[Lewy bodies]] within [[neuron]]s. Other potential factors involve [[genetic disease|genetic]] and environmental influences, medications, lifestyle, and prior health conditions.
Diagnosis is primarily based on [[signs and symptoms]], typically motor-related, identified through [[neurological examination]]. [[Medical imaging|Medical imaging techniques]] such as [[positron emission tomography]] can support the diagnosis. PD typically manifests in individuals over 60, with about one percent affected. In those younger than 50, it is termed "early-onset PD".
No cure for PD is known, and treatment focuses on alleviating symptoms. Initial treatment typically includes [[levodopa]], [[MAO-B inhibitor]]s, or [[dopamine agonist]]s. As the disease progresses, these medications become less effective and may cause [[dyskinesia|involuntary muscle movements]]. Diet and rehabilitation therapies can help improve symptoms. [[Deep brain stimulation]] is used to manage severe motor symptoms when drugs are ineffective. Little evidence exists for treatments addressing non-motor symptoms, such as sleep disturbances and mood instability. Life expectancy for those with PD is near-normal, but is decreased for early-onset.
{{TOC limit}}
== Classification and terminology ==
{{See also|Parkinsonism|Parkinson-plus syndrome}}
Parkinson's disease (PD) is a [[neurodegenerative disease]] affecting both the [[central nervous system|central]] and [[peripheral nervous systems]], characterized by the [[cell death|loss]] of [[dopamine]]-producing [[neurons]] in the [[substantia nigra]] region of the brain.{{Sfn|Ramesh|Arachchige|2023|pp=200–201, 203}} It is classified as a [[synucleinopathy]] due to the abnormal accumulation of the protein [[alpha-synuclein]], which aggregates into [[Lewy bodies]] within affected neurons.{{Sfn|Calabresi|Mechelli|Natale|Volpicelli-Daley|2023|pp=1,5}}
The loss of dopamine-producing neurons in the substantia nigra causes movement abnormalities, leading to Parkinson's further categorization as a [[movement disorder]].{{Sfn|National Institute of Neurological Disorders and Stroke}} In 30% of cases, disease progression leads to the cognitive decline, resulting in [[Parkinson's disease dementia]] (PDD).{{Sfn|Wallace|Segerstrom|van Horne|Schmitt|2022|p=149}} Alongside [[dementia with Lewy bodies]], PDD is one of the two subtypes of [[Lewy body dementia]].{{Sfn|Hansen|Ling|Lashley|Holton|2019|p=635}}
The four cardinal motor symptoms of Parkinson's—[[bradykinesia]] (slowed movements), [[postural instability]], [[Spasticity|rigidity]], and [[tremor]]—are called [[parkinsonism]].{{Sfn|Bhattacharyya|2017|p=7}}{{Sfn|Stanford University School Medicine}} These four symptoms are not exclusive to Parkinson's and can occur in many other conditions,{{Sfn|Bologna|Truong|Jankovic|2022|pp=1–6}} including [[HIV infection]] and [[MPTP#Discovery in users of illicit drugs|recreational drug use]].{{Sfn|Leta|Urso|Batzu|Lau|2022|p=1122}}{{Sfn|Langston|2017|p=S11}} Neurodegenerative diseases that feature parkinsonism, but have distinct differences are grouped under the umbrella of [[Parkinson-plus syndrome]]s, or alternatively, atypical parkinsonian disorders.{{Sfn|Prajjwal|Kolanu|Reddy|Ahmed|2024|pp=1–3}}{{Sfn|Olfatia|Shoeibia|Litvanb|2019|p=101}} PD can be attributed to [[Genetic disorder|genetic factors]], but most cases are [[idiopathic disease|idiopathic]], with no clearly identifiable cause.{{sfn|National Institute of Neurological Disorders and Stroke}}
== Signs and symptoms ==
{{Main|Signs and symptoms of Parkinson's disease}}
=== Motor ===
{{See also|Parkinsonism}}
{{multiple image
| align = right
| direction = vertical
| total_width = 200
| image1 = Paralysis agitans-Male Parkinson's victim-1892 cropped.png
| alt1 = The stooped posture of a patient with Parkinson's
| image2 = Writing by a Parkinson's disease patient.png
| alt2 = The small, jagged handwriting of a PD patient
| footer = Motor symptoms include a stooping posture, the [[Parkinsonian gait]], and [[Micrographia (handwriting)|micrographia]]—jagged, diminutive handwriting.
}}
A wide spectrum of motor and non-motor symptoms appears<!-- spectrum is singular --> in PD; the cardinal features are tremor, bradykinesia, rigidity, and postural instability, collectively termed [[parkinsonism]].{{sfn|Abusrair|Elsekaily|Bohlega|2022|p=2}} Appearing in 70–75% of those with PD,{{sfn|Abusrair|Elsekaily|Bohlega|2022|p=2}}{{sfn|Moustafa|Chakravarthy|Phillips|Gupta|2016|p=730}} tremor is often the predominant motor symptom.{{sfn|Abusrair|Elsekaily|Bohlega|2022|p=2}} Resting tremor is the most common, but kinetic tremors—occurring during voluntary movements—and postural tremor—preventing upright, stable posture—also occur.{{sfn|Moustafa|Chakravarthy|Phillips|Gupta|2016|p=730}} Tremor largely affects the hands and feet:{{sfn|Moustafa|Chakravarthy|Phillips|Gupta|2016|p=730}} a classic parkinsonian tremor is "[[pill-rolling]]", a resting tremor in which the thumb and index finger make contact in a circular motion at 4–6 Hz frequency.{{sfn|Abusrair|Elsekaily|Bohlega|2022|p=4}}{{sfn|Sveinbjornsdottir|2016|p=319}}
Bradykinesia describes difficulties in [[motor planning]], beginning, and executing, resulting in overall slowed movement with reduced amplitude that affects sequential and simultaneous tasks.{{sfn|Bologna|Paparella|Fasano|Hallett|2019|pp=727–729}} Bradykinesia can also lead to [[hypomimia]], reduced facial expressions.{{sfn|Sveinbjornsdottir|2016|p=319}} [[Spasticity|Rigidity]], also called rigor, refers to a feeling of stiffness and resistance to passive stretching of muscles.{{sfn|Moustafa|Chakravarthy|Phillips|Gupta|2016|p=728}} [[Postural instability]] typically appears in later stages, leading to [[balance disorder|impaired balance]] and [[falls in older adults|falls]].{{sfn|Palakurthi|Burugupally|2019|pp=1–2}} Postural instability also leads to a forward stooping posture.{{sfn|Palakurthi|Burugupally|2019|pp=1,4}}
Beyond the cardinal four, other motor deficits, termed secondary motor symptoms, commonly occur.{{sfn|Moustafa|Chakravarthy|Phillips|Gupta|2016|pp=727–728}} Notably, gait disturbances result in the [[parkinsonian gait]], which includes shuffling and [[Paroxysmal dyskinesia|paroxysmal deficits]], where a normal gait is interrupted by rapid footsteps—known as festination—or sudden stops, impairing balance and causing falls.{{sfn|Moustafa|Chakravarthy|Phillips|Gupta|2016|p=731}}{{sfn|Mirelman|Bonato|Camicioli|Ellis|2019|p=1}} Most people with PD experience speech problems, including [[stuttering]], [[Hypophonia|hypophonic, "soft" speech]], [[Dysarthria|slurring]], and festinating speech (rapid and poorly intelligible).{{sfn|Moustafa|Chakravarthy|Phillips|Gupta|2016|p=734}} Handwriting is commonly altered in PD, decreasing in size—known as [[micrographia (handwriting)|micrographia]]—and becoming jagged and sharply fluctuating.{{sfn|Moustafa|Chakravarthy|Phillips|Gupta|2016|p=732}} Grip and dexterity are also impaired.{{sfn|Moustafa|Chakravarthy|Phillips|Gupta|2016|p=733}}
=== Neuropsychiatric and cognitive ===
{| class="wikitable" style="float:right; margin-left:1em; font-size:90%; line-height:1.4em; width:400px;"
|+ {{sronly|Table featuring the prevalence of neuropsychiatric symptoms in PD}}
|+ Neuropsychiatric symptom prevalence in Parkinson's disease{{sfn|Aarslanda|Krambergera|2015|pp=660, 662}}
! rowspan="2" style="background:#33D2FD;color:black;text-align:center;" |Symptom
|-
! style="background:#33D2FD;color:black;" |Prevalence (%)
|-
! [[Anxiety]]
|style="text-align:center;"| 40–50
|-
! [[Apathy]]
|style="text-align:center;"| 40
|-
! [[Depression (mood)|Depression]]
|style="text-align:center;"| 20–40
|-
! [[Impulse control disorders]]
|style="text-align:center;"| 36–60
|-
! [[Psychosis]]
|style="text-align:center;"| 15–30
|-
|}
[[Neuropsychiatric]] symptoms such as [[anxiety]], [[apathy]], [[depression (mood)|depression]], [[hallucinations|hallucination]], and [[impulse control disorders]] occur in up to 60% of those with PD. They often precede motor symptoms and vary with disease progression.{{sfn|Aarslanda|Krambergera|2015|pp=659–660}} Non-motor fluctuations, including [[dysphoria]], [[fatigue]], and slowness of thought, are also common.{{sfn|Weintraub|Mamikonyan|2019|loc=sec. "Non-motor fluctuations"}} Some neuropsychiatric symptoms are not directly caused by neurodegeneration, but rather by its pharmacological management.{{sfn|Aarslanda|Krambergera|2015|p=660}}
Cognitive impairments rank among the most prevalent and debilitating non-motor symptoms.{{Sfn|Biundo|Weis|Antonini|2016|p=1}} These deficits may emerge in the early stages or before diagnosis,{{Sfn|Biundo|Weis|Antonini|2016|p=1}}{{Sfn|Gonzalez-Latapi|Bayram|Litvan|Marras|2021|p=74}} and their prevalence and severity tend to increase with disease progression. Ranging from [[mild cognitive impairment]] to severe [[Parkinson's disease dementia]], these impairments include [[executive dysfunction]], [[bradyphrenia|slowed cognitive processing speed]], and disruptions in time perception and estimation.{{Sfn|Gonzalez-Latapi|Bayram|Litvan|Marras|2021|p=74}}
=== Autonomic ===
[[Autonomic nervous system]] failures, known as [[dysautonomia]], can appear at any stage of PD.{{sfn|Palma|Kaufmann|2018|pp=372–373}}{{sfn|Pfeiffer|2020|p=1464}} They are among the most debilitating symptoms and greatly reduce quality of life.{{sfn|Palma|Kaufmann|2018|p=373}} Although almost all individuals with PD have cardiovascular autonomic dysfunction, only some are symptomatic.{{sfn|Palma|Kaufmann|2018|p=373}} Chiefly, [[orthostatic hypotension]]—a sustained [[blood pressure]] drop of at least 20 mmHg [[Systole|systolic]] or 10 mmHg [[diastolic]] after standing—occurs in 30–50% of cases. This can result in [[lightheadedness]] or [[Syncope (medicine)|fainting]]; subsequent falls are associated with higher morbidity and mortality.{{sfn|Palma|Kaufmann|2018|p=373}}{{sfn|Palma|Kaufmann|2020|loc=sec. "Synopsis", "Epidemiology", "Approach to the patient with orthostatic hypotension"}}
Other autonomic failures include [[gastrointestinal issues]] such as chronic constipation, [[gastroparesis|impaired stomach emptying]] and subsequent [[nausea]], [[hypersalivation|excessive salivation]], and [[dysphagia]] (difficulty swallowing); all greatly reduce quality of life.{{sfn|Pfeiffer|2020|pp=1465–1467}} Dysphagia, for instance, can prevent pill swallowing and lead to [[aspiration pneumonia]].{{sfn|Pfeiffer|2020|p=1468}} [[Urinary incontinence]], [[sexual dysfunction]], and [[Thermoregulation|thermoregulatory dysfunction]]—including heat and cold intolerance and excessive sweating—also frequently occur.{{sfn|Pfeiffer|2020|pp=1471–1473}}
===
Sensory deficits appear in up to 90% of people with PD and are usually present at early stages.{{Sfn|Zhu|Li|Ye|Jiang|2016|p=685}} [[Nociceptive pain|Nociceptive]] and [[neuropathic pain]] are common,{{Sfn|Zhu|Li|Ye|Jiang|2016|p=685}} with [[peripheral neuropathy]] affecting up to 55% of individuals.{{Sfn|Corrà|Vila-Chã|Sardoeira|Hansen|2023|pp=225–226}} [[Visual impairments]] are also frequently observed, including deficits in [[visual acuity]], [[color vision]], [[eye coordination]], and [[visual hallucinations]].{{Sfn|Zhu|Li|Ye|Jiang|2016|p=688}} An [[anosmia|impaired sense of smell]] is also prevalent.{{Sfn|Zhu|Li|Ye|Jiang|2016|p=687}} Individuals often struggle with spatial awareness, recognizing faces and emotions, and may experience challenges with reading and double vision.{{Sfn|Weil|Schrag|Warren|Crutch|2016|pp=2828, 2831–2832}}
[[Sleep disorder]]s are highly prevalent in PD, affecting up to 98%.{{Sfn|Stefani|Högl|2020|p=121}} These disorders include [[insomnia]], [[excessive daytime sleepiness]], [[restless legs syndrome]], [[REM sleep behavior disorder]] (RBD), and [[sleep-disordered breathing]], many of which can be worsened by medication. RBD may begin years before the initial motor symptoms. Individual presentation of symptoms varies, although most people affected by PD show an altered [[circadian rhythm]] at some point of disease progression.{{sfn|Dodet|Houot|Leu-Semenescu|Corvol|2024|p=1}}{{sfn|Bollu|Sahota|2017|pp=381–382}}
PD is also associated with a variety of [[skin disorder]]s that include [[melanoma]], [[seborrheic dermatitis]], [[bullous pemphigoid]], and [[rosacea]].{{sfn|Niemann|Billnitzer|Jankovic|2021|p=61}} Seborrheic dermatitis is recognized as a premotor feature that indicates dysautonomia and demonstrates that PD can be detected not only by changes of [[nervous tissue]], but also tissue abnormalities outside the nervous system.{{sfn|Almikhlafi|2024|p=7}}
== Causes ==
{{Main|Causes of Parkinson's disease}}
As of 2024, the cause of neurodegeneration in PD is unclear,{{sfn|Morris|Spillantini|Sue|Williams-Gray|2024}} though it is believed to result from the interplay of [[genetics|genetic]] and [[environmental factor|environmental]] factors.{{sfn|Morris|Spillantini|Sue|Williams-Gray|2024}} Most cases are [[idiopathic disease|idiopathic]] with no clearly identifiable cause, while about 5–10% are familial.{{sfn|Toffoli|Vieira|Schapira|2020|p=1}} Around a third of familial cases can be attributed to a single monogenic cause.{{sfn|Toffoli|Vieira|Schapira|2020|p=1}}
Molecularly, abnormal aggregation of alpha-synuclein is considered a key contributor to PD [[pathogenesis]],{{sfn|Morris|Spillantini|Sue|Williams-Gray|2024}} although the trigger for this aggregation is debated{{sfn|Brundin|Melki|2017|p=9808}} and some forms of PD do not include these aggregations.<ref>{{Cite journal |last1=Riederer |first1=Peter |last2=Nagatsu |first2=Toshiharu |last3=Youdim |first3=Moussa B. H. |last4=Wulf |first4=Max |last5=Dijkstra |first5=Johannes M. |last6=Sian-Huelsmann |first6=Jeswinder |date=May 2023 |title=Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson's disease |journal=Journal of Neural Transmission |language=en |volume=130 |issue=5 |pages=627–646 |doi=10.1007/s00702-023-02630-9 |issn=0300-9564 |pmc=10121516 |pmid=37062012}}</ref> Also, the vulnerability of substantia nigra pars compacta (SNc) dopaminergic neurons to oxidative stress, caused in part by intracellular dopamine being toxic, has been proposed as a major contributor to the disease.<ref>{{Cite journal |last1=Watanabe |first1=Hirohisa |last2=Dijkstra |first2=Johannes M. |last3=Nagatsu |first3=Toshiharu |date=2024-02-07 |title=Parkinson's Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges |journal=International Journal of Molecular Sciences |language=en |volume=25 |issue=4 |pages=2009 |doi=10.3390/ijms25042009 |doi-access=free |issn=1422-0067 |pmc=10888576 |pmid=38396687}}</ref> [[Proteostasis]] disruption and the dysfunction of cell [[organelles]], including [[endosomes]], [[lysosomes]], and [[mitochondria]], are implicated in pathogenesis.{{sfn|Morris|Spillantini|Sue|Williams-Gray|2024}} Additionally, maladaptive immune and inflammatory responses are potential contributors.{{sfn|Morris|Spillantini|Sue|Williams-Gray|2024}} The substantial heterogeneity in PD presentation and progression suggests the involvement of multiple interacting triggers and pathogenic pathways.{{sfn|Brundin|Melki|2017|p=9808}}
=== Genetic ===
[[File:Protein PARK2 PDB 1iyf.png|thumb|alt=A ribbon diagram of the protein parkin|[[Ribbon diagram]] of [[parkin (protein)|parkin]]]]
Parkinson's can be narrowly defined as a genetic disease, as rare inherited gene variants have been firmly linked to monogenic PD, and most cases carry variants that increase PD risk.{{sfn|Morris|Spillantini|Sue|Williams-Gray|2024}}{{sfn|Toffoli|Vieira|Schapira|2020|p=2}}{{sfn|Salles|Tirapegui|Chaná-Cuevas|2024|p=2}} PD [[heritability]] is estimated to range from 22 to 40%.{{sfn|Morris|Spillantini|Sue|Williams-Gray|2024}} Around 15% of diagnosed individuals have a [[family history (medicine)|family history]], of which 5–10% can be attributed to a causative risk gene [[mutation]]. Carrying one of these mutations may not lead to disease. Rates of familial PD vary by ethnicity; monogenic PD occurs in up to 40% of [[Arab-Berber]] and 20% of [[Ashkenazi Jewish]] people with PD.{{sfn|Salles|Tirapegui|Chaná-Cuevas|2024|p=2}}
As of 2024, around 90 genetic risk variants across 78 genomic loci have been identified.{{sfn|Farrow|Gokuladhas|Schierding|Pudjihartono|2024|p=1}} Notable risk variants include ''SNCA'' (which encodes alpha-synuclein), ''LRRK2'', and ''VPS35'' for [[autosomal dominant]] inheritance, and ''PRKN'', ''PINK1'', and ''DJ1'' for [[autosomal recessive]] inheritance.{{sfn|Morris|Spillantini|Sue|Williams-Gray|2024}}{{sfn|Bandres-Ciga|Diez-Fairen|Kim|Singleton|2020|p=2}} ''LRRK2'' is the most common autosomal dominant variant, responsible for 1–2% of all PD cases and 40% of familial cases.{{sfn|Tanner|Ostrem|2024}}{{sfn|Toffoli|Vieira|Schapira|2020|p=1}} [[Parkin (protein)|Parkin]] variants are associated with nearly half of recessive, early-onset monogenic PD.{{sfn|Toffoli|Vieira|Schapira|2020|pp=1–2}} Mutations in the ''GBA1'' gene, linked to [[Gaucher's disease]], can cause monogenic PD,{{sfn|Rossi|Schaake|Usnich|Boehm|2025|p=1-2}} and are associated with cognitive decline.{{sfn|Tanner|Ostrem|2024}}
=== Environmental ===
{{See also|Environmental health|Exposome}}
The limited heritability of Parkinson's strongly suggests environmental factors are involved, though identifying these risk factors and establishing [[causality]] is challenging due to PD's decade-long prodromal period.{{sfn|De Miranda|Goldmanb|Millerc|Greenamyred|2024|p=46}}
Environmental toxicants such as air pollution, pesticides, and industrial solvents like [[trichloroethylene]] are strongly linked to PD.{{sfn|Dorsey|Bloem|2024|pp=453–454}} Certain pesticides—such as [[paraquat]], [[glyphosate]], and [[rotenone]]—are the most established environmental toxicants for PD and are likely causal.{{sfn|Dorsey|Bloem|2024|p=454}}{{sfn|Bloem|Boonstra|2023|p=e948–e949}}{{sfn|Rietdijk|Perez-Pardo|Garssen|van Wezel|2017|p=1}} PD prevalence is strongly associated with local pesticide use, and many pesticides are mitochondrial toxins.{{sfn|Dorsey|Bloem|2024|pp=453–455}} Paraquat, for instance, structurally resembles metabolized [[MPTP]],{{sfn|Dorsey|Bloem|2024|p=454}} which selectively kills dopaminergic neurons by inhibiting [[mitochondrial complex 1]] and is widely used to [[animal models|model]] PD.{{sfn|Langston|2017|p=S14}}{{sfn|Dorsey|Bloem|2024|p=454}} Pesticide exposure after diagnosis may also accelerate disease progression.{{sfn|Dorsey|Bloem|2024|p=454}} Without high pesticide exposure, an estimated 20% of all PD cases would be prevented.{{sfn|Santos-Lobato|2024|p=1}}
=== Hypotheses ===
==== Prionic ====
The hallmark of PD is the formation of protein aggregates, beginning with alpha-synuclein fibrils and followed by Lewy bodies and Lewy neurites.{{sfn|Wu|Schekman|2024|p=1}} The [[prion]] hypothesis suggests that alpha-synuclein aggregates are pathogenic and can spread to neighboring, healthy neurons and seed new aggregates. Some propose that the heterogeneity of PD may stem from different "strains" of alpha-synuclein aggregates and varying anatomical sites of origin.{{sfn|Brundin|Melki|2017|p=9809}}{{sfn|Vázquez-Vélez|Zoghbi|2021|p=96}} Alpha-synuclein propagation has been demonstrated in cell and animal models and is the most popular explanation for the progressive spread through specific neuronal systems.{{sfn|Dickson|2018|p=S31}} However, therapeutic efforts to clear alpha-synuclein have failed.{{sfn|Wu|Schekman|2024|pp=1–2}} Additionally, postmortem brain tissue analysis shows that alpha-synuclein pathology does not clearly progress through the nearest neural connections.{{sfn|Brundin|Melki|2017|p=9812}}
==== Braak's ====
{{Main|Parkinson's disease and gut-brain axis#Braak's hypothesis}}
In 2002, [[Heiko Braak]] and colleagues proposed that PD begins outside the brain and is triggered by a "neuroinvasion" of some unknown pathogen.{{sfn|Dorsey|De Miranda|Horsager|Borghammer|2024|p=363}}{{sfn|Rietdijk|Perez-Pardo|Garssen|van Wezel|2017|p=2}} The pathogen enters through the nasal cavity and is swallowed into the digestive tract, initiating Lewy pathology in both areas.{{sfn|Rietdijk|Perez-Pardo|Garssen|van Wezel|2017|p=1}}{{sfn|Dorsey|De Miranda|Horsager|Borghammer|2024|p=363}} This alpha-synuclein pathology may then travel from the gut to the central nervous system through the [[vagus nerve]].{{sfn|Rietdijk|Perez-Pardo|Garssen|van Wezel|2017|p=3}} This theory could explain the presence of Lewy pathology in both the enteric nervous system and olfactory tract neurons, as well as clinical symptoms such as loss of smell and gastrointestinal problems.{{sfn|Rietdijk|Perez-Pardo|Garssen|van Wezel|2017|p=2}} Environmental toxicants ingested in a similar manner might also trigger PD.{{sfn|Dorsey|De Miranda|Horsager|Borghammer|2024|pp=363–364, 371–372}}
=== Risk factors ===
As 90% of PD cases are idiopathic, the identification of the risk factors that may influence disease progression or severity is critical.{{sfn|Ascherio |Schwarzschild|2016|p=1257}}{{sfn|De Miranda|Goldmanb|Millerc|Greenamyred|2024|p=46}} The most significant risk factor in developing PD is age, with a prevalence of 1% in those over 65 and around 4.3% in those over 85.{{sfn|Coleman|Martin|2022|pp=2321–2322}} [[Traumatic brain injury]] significantly increases PD risk, especially if recent.{{sfn|Ascherio|Schwarzschild|2016|p=1260}}{{sfn|Delic|Beck|Pang|Citron|2020|pp=1–2}} Dairy consumption correlates with a higher risk, possibly due to contaminants such as [[heptachlor epoxide]].{{sfn|Ascherio |Schwarzschild|2016|p=1259}} Although the connection is unclear, [[melanoma]] diagnosis is associated with a roughly 45% risk increase.{{sfn|Ascherio |Schwarzschild|2016|p=1259}} Also, an association was found between [[methamphetamine]] use and PD risk.{{sfn|Ascherio|Schwarzschild|2016|p=1259}}
=== Protective factors ===
Although no compounds or activities have been mechanistically established as [[neuroprotection|neuroprotective]] for PD,{{Sfn|Crotty|Schwarzschild|2020|p=1}}{{Sfn|Fabbri|Rascol|Foltynie|Carroll|2024|p=2}} several factors have been found to be associated with a decreased risk.{{Sfn|Crotty|Schwarzschild|2020|p=1}} [[Tobacco|Tobacco use]] and [[Tobacco smoking|smoking]] are strongly associated with a decreased risk, reducing the chance of developing PD by up to 70%.{{Sfn|Ascherio|Schwarzschild|2016|p=1262}}{{Sfn|Grotewolda|Albina|2024|pp=1–2}}{{sfn|Ascherio |Schwarzschild|2016|p=1259}} Various tobacco and smoke components have been hypothesized to be neuroprotective, including [[nicotine]], [[carbon monoxide]], and [[Monoamine oxidase inhibitor|monoamine oxidase B inhibitors]].{{Sfn|Grotewolda|Albina|2024|p=2}}{{Sfn|Rose|Schwarzschild|Gomperts|2024|pp=268–269}} Consumption of [[caffeine]] as an ingredient of [[coffee]] or [[tea]] is also strongly associated with neuroprotection.{{Sfn|Grotewolda|Albina|2024|p=3}}
Although findings have varied, usage of [[nonsteroidal anti-inflammatory drugs]] (NSAIDs) such as [[ibuprofen]] may be neuroprotective.{{Sfn|Singh|Tripathi|Singh|2021|p=10}}{{Sfn|Ascherio|Schwarzschild|2016|pp=1265–1266}} [[Calcium channel blockers]] may also have a protective effect, with a 22% risk reduction reported.{{Sfn|Lin|Pang|Li|Ou|2024|p=1}} Higher blood concentrations of [[urate]]—a potent [[antioxidant]]—have been proposed to be neuroprotective.{{Sfn|Grotewolda|Albina|2024|p=2}}{{Sfn|Ascherio|Schwarzschild|2016|p=1263}} Although longitudinal studies observe a slight decrease in PD risk among those who consume [[Alcoholic beverage|alcohol]]—possibly due to alcohol's urate-increasing effect—alcohol abuse may increase risk.{{Sfn|Ascherio|Schwarzschild|2016|p=1261}}
== Pathophysiology ==
{{Main|Pathophysiology of Parkinson's disease}}
[[File:Blausen 0704 ParkinsonsDisease.png|thumb|upright=1.5|Parkinson's results from the death of [[dopamine]]-releasing [[neuron]]s in the [[substantia nigra pars compacta]], seen by the loss of dark [[neuromelanin]] in the lower inset.]]
Parkinson's disease has two hallmark pathophysiological processes: the abnormal aggregation of alpha-synuclein that leads to Lewy pathology, and the degeneration of dopaminergic neurons in the [[substantia nigra pars compacta]].{{sfn|Pardo-Moreno|García-Morales|Suleiman-Martos|Rivas-Domínguez|2023|p=3}}{{sfn|Vázquez-Vélez|Zoghbi|2021|p=88}} The death of these neurons reduces available dopamine in the [[striatum]], which in turn affects circuits controlling movement in the [[basal ganglia]].{{sfn|Vázquez-Vélez|Zoghbi|2021|p=88}} By the time motor symptoms appear, 50–80% of all dopaminergic neurons in the substantia nigra have degenerated.{{sfn|Vázquez-Vélez|Zoghbi|2021|p=88}}
Cell death and Lewy pathology, though, are not limited to the substantia nigra.{{sfn|Dickson|2018|p=S32}} The [[Braak staging|six-stage Braak system]] holds that alpha-synuclein pathology begins in the [[olfactory bulb]] or outside the central nervous system in the [[enteric nervous system]] before ascending the brain stem.{{sfn|Ye|Robak|Yu|Cykowski|2023|p=98}} In the third Braak stage, Lewy body pathology appears in the substantia nigra,{{sfn|Ye|Robak|Yu|Cykowski|2023|p=98}} and by the sixth step, Lewy pathology has spread to the limbic and neocortical regions.{{sfn|Vázquez-Vélez|Zoghbi|2021|p=93}} Although Braak staging offers a strong basis for PD progression, around 50% of individuals do not follow the predicted model.{{sfn|Henderson|Trojanowski|Lee|2019|p=2}} Lewy pathology is highly variable and may be entirely absent in some persons with PD.{{sfn|Dickson|2018|p=S32}}{{sfn|Ye|Robak|Yu|Cykowski|2023|p=96}}
=== Alpha-synuclein pathology ===
{{Further|Protein aggregation|Lewy body}}
[[File:Lewy bodies (alpha synuclein inclusions).jpg|thumb|upright=1.2|[[Lewy bodies|Lewy bodies and Lewy neurites]] stained brown in PD brain tissue]]
Alpha-synuclein is an intracellular protein typically localized to [[presynaptic terminals]] and involved in [[synaptic vesicle trafficking]], [[intracellular transport]], and [[neurotransmitter release]].{{sfn|Henderson|Trojanowski|Lee|2019|p=2}}{{sfn|Chen|Gu|Wang|2022}} When [[misfolded]], it can aggregate into [[oligomer]]s and [[protofibril]]s{{clarify|date=July 2025}} that in turn lead to Lewy body formation.{{sfn|Chen|Gu|Wang|2022}}{{sfn|Menšíková|Matěj|Colosimo|Rosales|2022|p=8}}{{sfn|Borghammer|2018|p=5}} Due to their lower [[Molar mass|molecular weight]], oligomers and protofibrils may disseminate and be transmitted to other cells more rapidly.{{sfn|Borghammer|2018|p=5}}
Lewy bodies consist of a fibrillar exterior and a granular core. Although alpha-synuclein is the dominant [[wikt:proteinaceous|proteinaceous]] component, the core contains mitochondrial and autophagosomal membrane components, suggesting a link with organelle dysfunction.{{sfn|Vázquez-Vélez|Zoghbi|2021|p=95}}{{sfn|Vázquez-Vélez|Zoghbi|2021|p=89}} Whether Lewy bodies themselves contribute to or are simply the result of PD pathogenesis is unclear; alpha-synuclein oligomers can independently mediate cell damage, and neurodegeneration can precede Lewy body formation.{{sfn|Menšíková|Matěj|Colosimo|Rosales|2022|p=6}}
=== Pathways involved in neurodegeneration ===
{{See also|Neurodegeneration#Mechanisms}}
Three major pathways—[[vesicular trafficking]], [[Lysosome|lysosomal degradation]], and mitochondrial maintenance—are known to be affected by and contribute to PD pathogenesis, with all three linked to alpha-synuclein.{{sfn|Vázquez-Vélez|Zoghbi|2021|pp=96–99}} High-risk gene variants also impair all three of these processes.{{sfn|Vázquez-Vélez|Zoghbi|2021|pp=96–99}} All steps of vesicular trafficking are impaired by alpha-synuclein. It blocks [[endoplasmic reticulum]] (ER) vesicles from reaching the [[Golgi apparatus|Golgi]]—leading to [[XBP1#endoplasmic reticulum stress response|ER stress]]—and Golgi vesicles from reaching the [[lysosome]], preventing alpha-synuclein degradation and leading to its build-up.{{sfn|Vázquez-Vélez|Zoghbi|2021|pp=96–97}} Risky gene variants, chiefly ''GBA'', further compromise lysosomal function.{{sfn|Vázquez-Vélez|Zoghbi|2021|pp=98–99}} Although the mechanism is not well established, alpha-synuclein can impair mitochondrial function and cause subsequent [[oxidative stress]]. Mitochondrial dysfunction can, in turn, lead to further alpha-synuclein accumulation in a [[positive feedback loop]].{{sfn|Vázquez-Vélez|Zoghbi|2021|p=99}} Microglial activation, possibly caused by alpha-synuclein, is also strongly indicated.{{sfn|Vázquez-Vélez|Zoghbi|2021|p=100}}{{sfn|Ye|Robak|Yu|Cykowski|2023|p=112}}
==== Mitochondrial dysfunction ====
{{See also|Mitochondrial disease}}
Mitochondrial dysfunction is well-established in PD.{{sfn|Borsche|Pereira|Klein|Grünewald|2021|p=45}} Increased [[oxidative stress]] and reduced [[calcium buffering]] may contribute to neurodegeneration.{{sfn|Borsche|Pereira|Klein|Grünewald|2021|p=46, 51–53}} The finding that [[MPP+|MPP<sup>+</sup>]]—a [[respiratory complex I]] inhibitor and MPTP metabolite—caused parkinsonian symptoms strongly implied that mitochondria contributed to PD pathogenesis.{{sfn|Borsche|Pereira|Klein|Grünewald|2021|p=45}}<!--Alpha-synuclein and toxicants like [[rotenone]] similarly disrupt respiratory complex I. SOURCE NEEDED--> Additionally, faulty gene variants involved in familial PD—including ''PINK1'' and ''Parkin''—prevent the elimination of dysfunctional mitochondria through [[mitophagy]].{{sfn|Borsche|Pereira|Klein|Grünewald|2021|pp=47–49}}
==== Neuroinflammation ====
Some hypothesize that neurodegeneration arises from a chronic [[Neuroimmune system|neuroinflammatory state]] created by local activated [[microglia]] and infiltrating immune cells.{{sfn|Morris|Spillantini|Sue|Williams-Gray|2024}} Mitochondrial dysfunction may also drive immune activation, particularly in monogenic PD.{{sfn|Morris|Spillantini|Sue|Williams-Gray|2024}} Some [[autoimmune disorders]] increase the risk of developing PD, supporting an autoimmune contribution.{{sfn|Tan|Chao|West|Chan|2020|p=303}} Additionally, [[influenza]] and [[herpes simplex virus]] infections increase the risk of PD, possibly due to a [[molecular mimicry|viral protein resembling]] alpha-synuclein.{{sfn|Tan|Chao|West|Chan|2020|p=304}} PD risk is also decreased with [[immunosuppressants]].{{sfn|Morris|Spillantini|Sue|Williams-Gray|2024}}
== Diagnosis ==
Diagnosis of PD is largely clinical, relying on [[medical history]] and examination of symptoms, with an emphasis on symptoms that appear in later stages.{{sfn|Armstrong|Okun|2020|p=548}}{{sfn|Rizzo|Copetti|Arcuti|Martino|2016|p=1}} Although early-stage diagnosis is not reliable,{{sfn|Rizzo|Copetti|Arcuti|Martino|2016|p=1}}{{sfn|Ugrumov|2020|p=997}} prodromal diagnosis may consider previous family history of PD and possible early symptoms such as [[rapid eye movement sleep behavior disorder]] (RBD), reduced [[Olfaction|sense of smell]], and gastrointestinal issues.{{sfn|Armstrong|Okun|2020|p=551}} Isolated RBD is a particularly significant sign, as 90% of those affected will develop some form of neurodegenerative parkinsonism.{{sfn|Tolosa|Garrido|Scholz|Poewe|2021|p=391}} Diagnosis in later stages requires the manifestation of parkinsonism, specifically bradykinesia and rigidity or tremor. Further support includes other motor and non-motor symptoms and genetic profiling.{{sfn|Armstrong|Okun|2020|pp=551–552}}
A PD diagnosis is typically confirmed by any two of these criteria: responsiveness to levodopa, resting tremor, levodopa-induced dyskinesia, or [[DaT scan|dopamine transporter single-proton emission computed tomography]] confirmation.{{sfn|Armstrong|Okun|2020|pp=551–552}} If these criteria are not met, atypical parkinsonism is considered.{{sfn|Armstrong|Okun|2020|p=551}} Definitive diagnoses can only be made [[autopsy|post mortem]] through pathological analysis.{{sfn|Rizzo|Copetti|Arcuti|Martino|2016|p=1}} Misdiagnosis is common, with a reported error rate near 25%, and diagnoses often change during follow-ups.{{sfn|Rizzo|Copetti|Arcuti|Martino|2016|p=1}}{{sfn|Heim|Krismer|De Marzi|Seppi|2017|p=916}} Diagnosis can be further complicated by multiple overlapping conditions.{{sfn|Rizzo|Copetti|Arcuti|Martino|2016|p=1}}
=== Imaging ===
[[File:Reduced striatal 18F-DOPA uptake.png|thumb|upright=1.4|Reduced [[Radionuclide|radioisotopic]] [[Fluorodopa|F-DOPA]] uptake in the [[striatum]] of a PD patient, captured through [[Positron emission tomography|PET]]]]
Diagnosis can be aided by molecular imaging techniques such as [[magnetic resonance imaging]] (MRI), [[positron emission tomography]] (PET), and [[single-photon emission computed tomography]] (SPECT).{{sfn|Bidesi|Andersen|Windhorst|Shalgunov|2021|p=660}}{{sfn|Boonstra|Michielse|Temel|Hoogland|2020|p=175}} As both conventional MRI and [[CT scan|computed tomography]] (CT) scans are usually normal in early PD, they can be used to exclude other pathologies that cause parkinsonism.{{sfn|Heim|Krismer|De Marzi|Seppi|2017|p=916}}{{sfn|Brooks|2010|p=597}} [[Diffusion-weighted magnetic resonance imaging|Diffusion MRI]] can differentiate PD from [[multiple system atrophy]].{{sfn|Tolosa|Garrido|Scholz|Poewe|2021|p=392}} Emerging MRI techniques of at least 3.0 T [[magnetic resonance imaging#Construction and physics|field strength]]—including [[MRI sequence#Neuromelanin imaging|neuromelanin-MRI]], [[Magnetic resonance spectroscopic imaging|1H-MRSI]], and [[resting state fMRI]]—may detect abnormalities in the substantia nigra, nigrostriatal pathway, and elsewhere.{{sfn|Heim|Krismer|De Marzi|Seppi|2017|p=916}}
Unlike MRI, PET and SPECT use [[radionuclide|radioisotopes]] for imaging.{{sfn|Bidesi|Andersen|Windhorst|Shalgunov|2021|p=665}} Both techniques can aid diagnosis by characterizing PD-associated alterations in the metabolism and [[dopamine transporter|transport]] of dopamine in the basal ganglia.{{sfn|Suwijn|van Boheemen|de Haan|Tissingh|2015}}{{sfn|Bidesi|Andersen|Windhorst|Shalgunov|2021|pp=664–672}} Largely used outside the United States, iodine-123-meta-iodobenzylguanidine [[myocardium|myocardial]] [[scintigraphy]] can assess heart muscle denervation to support a PD diagnosis.{{sfn|Armstrong|Okun|2020|p=552}}
=== Differential diagnosis ===
{{See also|Parkinson-plus syndrome}}
[[Differential diagnosis]] of Parkinson's is among the most difficult in [[neurology]].{{sfn|Heim|Krismer|De Marzi|Seppi|2017|p=915}} Differentiating early PD from [[Parkinson-plus syndrome|atypical parkinsonian disorder]]s is a major difficulty. In their initial stages, PD can be difficult to distinguish from the atypical neurodegenerative parkinsonisms, including [[multiple system atrophy]], [[dementia with Lewy bodies]], and the [[tauopathies]] [[progressive supranuclear palsy]] and [[corticobasal degeneration]].{{sfn|Tolosa|Garrido|Scholz|Poewe|2021|p=389}}{{sfn|Caproni|Colosimo|2020|p=21}} Other conditions that may present similarly to PD include vascular Parkinsonism, [[Alzheimer's disease]], and [[frontotemporal dementia]].{{sfn|Tolosa|Garrido|Scholz|Poewe|2021|p=390}}{{sfn|Caproni|Colosimo|2020|pp=15, 21}}
The International Parkinson and Movement Disorder Society has proposed a set of criteria that, unlike the standard Queen's Square Brain Bank Criteria, includes non-exclusionary "red-flag" clinical features that may not suggest PD.{{sfn|Tolosa|Garrido|Scholz|Poewe|2021|pp=390–391}} A large number of "red flags" has<!-- number is singular --> been proposed and adopted for various conditions that might mimic the symptoms of PD.{{sfn|Caproni|Colosimo|2020|p=14}} Diagnostic tests, including gene sequencing, molecular imaging techniques, and assessment of smell may also distinguish PD.{{sfn|Tolosa|Garrido|Scholz|Poewe|2021|p=392}} MRI is particularly powerful due to several unique features for atypical parkinsonisms.{{sfn|Tolosa|Garrido|Scholz|Poewe|2021|p=392}}
{| class="wikitable plainrowheaders"
|-
!scope="col" | Disorder
!scope="col" | Distinguishing symptoms and features{{sfn|Tolosa|Garrido|Scholz|Poewe|2021|p=391}}{{Sfn|Simon|Greenberg|Aminoff|2017}}{{Sfn|Greenland|Barker|2018}}
|-
! scope="row" | [[Corticobasal syndrome]]
| Levodopa resistance, [[myoclonus]], [[dystonia]], corticosensory loss, [[Alien hand syndrome|alien limb phenomenon]], [[apraxia]], and [[non-fluent aphasia]]
|-
! scope="row" | [[Dementia with Lewy bodies]]
| Levodopa resistance, cognitive predominance before motor symptoms, and fluctuating cognitive symptoms
|-
! scope="row" | [[Essential tremor]]
| Tremor that worsens with action, normal SPECT scan
|-
! scope="row" | [[Multiple system atrophy]]
| Levodopa resistance, rapidly progressive, autonomic failure, stridor, present [[Plantar reflex|Babinski sign]], cerebellar ataxia, and specific MRI findings like the "Hot Cross Bun"
|-
! scope="row" | [[Progressive supranuclear palsy]]
| Levodopa resistance, restrictive vertical gaze, [[Pseudobulbar affect|pseudobulbar crying]], [[Blepharospasm|eyelid twitching]], specific MRI findings, and early and different postural difficulties
|-
|}
== Management ==
{{Main|Management of Parkinson's disease}}
As of 2025, no disease-modifying therapies exist that reverse or slow neurodegeneration.{{Sfn|Crotty|Schwarzschild|2020|p=1}}{{Sfn|Fabbri|Rascol|Foltynie|Carroll|2024|p=2}} Management typically combines lifestyle modifications with [[physical therapy]].{{sfn|Connolly|Lang|2014}} Current pharmacological interventions purely target symptoms, by either increasing endogenous [[dopamine]] levels or directly mimicking dopamine's effect on the patient's brain.{{sfn|de Bie|Clarke|Espay|Fox|2020|p=3}}{{sfn|Connolly|Lang|2014}} These include dopamine agonists, MAO-B inhibitors, and levodopa—the most widely used and effective drug.{{sfn|de Bie|Clarke|Espay|Fox|2020|pp=1, 3}}{{sfn|Connolly|Lang|2014}} The optimal time to initiate pharmacological treatment is debated,{{sfn|Kobylecki|2020|p=395}} but initial dopamine agonist and MAO-B inhibitor treatment and later levodopa therapy are common.{{sfn|de Bie|Clarke|Espay|Fox|2020|p=4}} Invasive procedures such as [[deep brain stimulation]] may be used when medications are ineffective.{{sfn|Limousin|Foltynie|2019|p=234}}{{sfn|Bronstein|Tagliati|Alterman|Lozano|2011|p=169}}
=== Medications ===
==== Levodopa ====
[[File:Stalevo.jpg|thumb|upright=0.8|LCE ([[levodopa]]/[[carbidopa]]/[[entacapone]]) pills contain a cocktail of the dopamine precursor levadopa and COMT and AAAD inhibitors.]]
[[Levodopa]] is the most widely used and most effective therapy—the [[Gold standard (test)|gold standard]]—for PD treatment.{{sfn|de Bie|Clarke|Espay|Fox|2020|pp=1, 3}} The compound occurs naturally and is the immediate precursor for dopamine synthesis in the dopaminergic neurons of the substantia nigra.{{sfn|Tambasco|Romoli|Calabresi|2018|p=1239}} Levodopa administration reduces the dopamine deficiency in parkinsonism.{{sfn|LeWitt|Fahn|2016|p=S5-S6}}{{sfn|Tambasco|Romoli|Calabresi|2018|pp=1239–1240}}
Despite its efficacy, levodopa poses several challenges. Its administration has been called the "pharmacologist's nightmare".{{sfn|Tambasco|Romoli|Calabresi|2018|p=1240}}{{sfn|Leta|Klingelhoefer|Longardner|Campagnolo|2023|p=1466}} Its metabolism outside the brain by [[aromatic L-amino acid decarboxylase]] <!-- (AAAD) --> and [[catechol-O-methyltransferase]] <!-- (COMT) --> can cause nausea and vomiting; inhibitors such as [[carbidopa]], [[entacapone]], and [[benserazide]] are usually taken with levodopa to mitigate these effects.{{sfn|Leta|Klingelhoefer|Longardner|Campagnolo|2023|pp=1466–1468}}{{sfn|Tambasco|Romoli|Calabresi|2018|p=1241}}{{efn|group=note|These inhibitors do not cross the [[blood brain barrier]], thus do not prevent levodopa metabolism there.{{sfn|Leta|Klingelhoefer|Longardner|Campagnolo|2023|p=1468}}}} Long-term levodopa use may also [[Levodopa-induced dyskinesia|induce dyskinesia]] and motor fluctuations. Although this often causes levodopa use to be delayed to later stages, earlier administration leads to improved motor function and quality of life.{{sfn|de Bie|Clarke|Espay|Fox|2020|pp=1, 3–4}}
==== Dopamine agonists ====
[[Dopamine agonists]] are an alternative or complement to levodopa therapy. They activate dopamine receptors in the striatum, with reduced risk of motor fluctuations and dyskinesia, and are efficacious in both early- and late-stage PD.{{sfn|Jing|Yang|Taximaimaiti|Wang|2023|p=1226}} The agonist [[apomorphine]] is often used for drug-resistant OFF time in later-stage PD.{{sfn|Jing|Yang|Taximaimaiti|Wang|2023|p=1226}}{{sfn|Kobylecki|2020|p=396}} After five years of use, impulse-control disorders may occur in over 40% of those taking dopamine agonists.{{sfn|Kobylecki|2020|p=395}} A problematic, narcotic-like withdrawal effect may occur when agonist use is reduced or stopped.{{sfn|Kobylecki|2020|p=395}}{{sfn|de Bie|Clarke|Espay|Fox|2020|p=1}} Compared to levodopa, dopamine agonists are more likely to cause fatigue, daytime sleepiness, and hallucinations.{{sfn|de Bie|Clarke|Espay|Fox|2020|p=1}}
==== MAO-B inhibitors ====
MAO-B inhibitors—such as [[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.{{sfn|Robakis|Fahn|2015|pp=433–434}} These compounds mildly alleviate motor symptoms when used as monotherapy, but can also be used with levodopa and at any disease stage.{{sfn|Robakis|Fahn|2015|p=433}} Common side effects are nausea, dizziness, insomnia, sleepiness, and orthostatic hypotension.{{sfn|Armstrong|Okun|2020}} MAO-Bs are known to increase serotonin and cause a potentially dangerous condition known as [[serotonin syndrome]].{{sfn|Robakis|Fahn|2015|p=435}}
==== Other drugs ====
Treatments for non-motor symptoms of PD have not been well studied, and many medications are used [[off-label]].{{sfn|Tanner|Ostrem|2024}} A diverse range of symptoms beyond those related to motor function can be treated pharmaceutically.{{sfn|The National Collaborating Centre for Chronic Conditions}} Examples include [[Acetylcholinesterase inhibitor|cholinesterase inhibitors]] for cognitive impairment and [[modafinil]] for [[excessive daytime sleepiness]].{{sfn|Seppi|Ray Chaudhuri|Coelho|Fox|2019|pp=183, 185, 188}} [[Fludrocortisone]], [[midodrine]], and [[droxidopa]] are commonly used off-label for orthostatic hypotension related to autonomic dysfunction. Sublingual [[atropine]] or [[botulinum toxin]] injections may be used off-label for drooling. [[SSRIs]] and [[SNRIs]] are often used for depression related to PD, but a risk exists of [[serotonin syndrome]] with the SSRI or SNRI antidepressants.{{sfn|Tanner|Ostrem|2024}} Doxepin and rasagline may reduce physical fatigue in PD.{{sfn|Elbers|Verhoef|van Wegen|Berendse|2015}}
=== Invasive interventions ===
[[File:Parkinson surgery.jpg|upright|thumb|Placement of an electrode into the brain for [[deep brain stimulation]]]]
Surgery for PD first appeared in the 19th century, and by the 1960s, had evolved into [[ablative brain surgery]] that lesioned the [[basal ganglia]], [[thalamus]], or [[globus pallidus]] (a [[pallidotomy]]).{{sfn|Lozano|Tam|Lozano|2018|pp=1–2}} The discovery of levadopa for PD treatment caused ablative therapies to largely disappear.{{sfn|Lozano|Tam|Lozano|2018|p=2}}{{sfn|Bronstein|Tagliati|Alterman|Lozano|2011|p=165}} Ablative surgeries experienced a resurgence in the 1990s, but were quickly superseded by newly developed [[deep brain stimulation]] (DBS).{{sfn|Bronstein|Tagliati|Alterman|Lozano|2011|p=165}} Although [[gamma knife]] and [[high-intensity focused ultrasound]] surgeries have been developed for pallidotomies and [[thalamotomies]], their use is rare as of 2025.{{sfn|Lozano|Tam|Lozano|2018|p=6}}{{sfn|Moosa|Martínez-Fernández|Elias|del Alamo|2019|pp=1244–1249}}{{fv|reason=Article does not, at a casual look, seem to discuss frequency of use of focused ultrasound|date=April 2025}}
DBS involves the implantation of [[electrodes]] called [[Neurostimulation|neurostimulator]]s, which send electrical impulses to specific parts of the brain.{{sfn|Limousin|Foltynie|2019|p=234}} DBS for the [[subthalamic nucleus]] and [[globus pallidus interna]] has high efficacy for up to 2 years, but long-term efficacy is unclear and likely decreases with time.{{sfn|Limousin|Foltynie|2019|p=234}} DBS typically targets rigidity and tremor,{{sfn|Bronstein|Tagliati|Alterman|Lozano|2011|p=168}} and is recommended for PD patients who are intolerant or do not respond to medication.{{sfn|Bronstein|Tagliati|Alterman|Lozano|2011|p=169}} Cognitive impairment is the most common exclusion criteria.{{sfn|Bronstein|Tagliati|Alterman|Lozano|2011|p=166}}
=== Rehabilitation ===
{{Further|Management of Parkinson's disease#Rehabilitation}}
Although pharmacological therapies can improve symptoms, autonomy, and the ability to perform everyday tasks is still reduced by PD. Rehabilitation is often useful, but the scientific support for any single rehabilitation treatment is limited.{{sfn|Tofani|Ranieri|Fabbrini|Berardi|2020|p=891}}
Exercise programs are often recommended, with preliminary evidence of efficacy.{{sfn|Ernst|Folkerts|Gollan|Lieker|2023}}{{Sfn|Crotty|Schwarzschild|2020|pp=1–2}}{{sfn|Ahlskog|2011|p=292}} Regular [[physical exercise]] with or without physical therapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.{{sfn|Ernst|Folkerts|Gollan|Lieker|2023}} Aerobic, mind-body, and resistance training may be beneficial in alleviating PD-associated depression and anxiety.{{sfn|Ahlskog|2011|p=292}}{{sfn|Costa|Prati|de Oliveira|Brito|2024}} [[Strength training]] may increase [[manual dexterity]] and strength, facilitating daily tasks that require grasping objects.{{sfn|Ramazzina|Bernazzoli|Costantino|2017|pp=620–623}} Aerobic exercise, resistance training, and balance- and task-specific training have been found to improve strength, [[VO2 max|VO<sub>2</sub> Max]] and balance. While flexibility training is commonly used, it has a lower strength of recommendation compared to aerobic and resistance training.{{sfn|Osborne|Botkin|Colon-Semenza|DeAngelis|2022|pp=3,7-10,14}}
[[File:Three Wheeler.jpg|left|thumb|alt=A Parkinson's patient on a tricycle|Exercise, like the [[tricycle]] ride of this PD patient, is often recommended.]]
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]].{{Sfn|O'Sullivan|Schmitz|2007|pp=873, 876}} Deep diaphragmatic breathing may also improve chest-wall mobility and [[vital capacity]] decreased by the stooped posture and respiratory dysfunctions of advanced Parkinson's.{{Sfn|O'Sullivan|Schmitz|2007|p=880}} Rehabilitation techniques targeting gait and the challenges posed by bradykinesia, shuffling, and decreased arm swing include [[Nordic walking|pole walking]], [[Treadmill|treadmill walking]], and [[marching]] exercises.{{Sfn|O'Sullivan|Schmitz|2007|p=879}} Long-term physiotherapy (greater than six months) reduces the need for antiparkinsonian medication; multidisciplinary rehabilitation programs combined with physiotherapy can result in reduction in the levodopa-equivalent dose.{{sfn|Okada|Ohtsuka|Kamata|Yamamoto|2021|pp=1619-1620, 1624-1625}}
[[Speech therapies]] such as the [[Lee Silverman voice treatment]] may reduce the effect of speech disorders associated with PD.{{sfn|McDonnell|Rischbieth|Schammer|Seaforth|2018|pp=607–609}} [[Occupational therapy]] as a rehabilitation strategy can improve quality of life by enabling people with PD to find engaging activities and communal roles, adapt to their living environment, and improve domestic and work abilities.{{sfn|Tofani|Ranieri|Fabbrini|Berardi|2020|pp=891, 900}}
=== Diet ===
PD poses digestive problems such as constipation and [[gastroparesis|prolonged emptying of stomach contents]], and a balanced diet with periodical nutritional assessments is recommended to avoid weight loss or gain and minimize the consequences of gastrointestinal dysfunction. In particular, a Mediterranean diet is advised and may slow disease progression.{{sfn|Lister|2020|pp=99–100}}{{sfn|Barichella|Cereda|Pezzoli|2009|pp=1888}} As it can compete for uptake with [[amino acids]] derived from protein, levodopa should be taken 30 minutes before meals to minimize such competition. Low-protein diets may also be needed by later stages.{{sfn|Barichella|Cereda|Pezzoli|2009|pp=1888}} As the disease advances, swallowing difficulties often arise. Using [[thickening agent]]s 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.{{sfn|Barichella|Cereda|Pezzoli|2009|pp=1887}}{{sfn|Pasricha|Guerrero-Lopez|Kuo|2024|p=212}} Increased water and fiber intakes are used to treat constipation.{{sfn|Pasricha|Guerrero-Lopez|Kuo|2024|p=216}}
=== Palliative care ===
As PD is incurable, palliative care aims to improve the quality of life for both the patient and family by alleviating the symptoms and stress associated with illness.{{sfn|Ghoche|2012|pp=S2-S3}}{{sfn|Wilcox|2010|p=26}}{{sfn|Ferrell|Connor|Cordes|Dahlin|2007|p=741}} Early integration of palliative care into the disease course is recommended, rather than delaying until later stages.{{sfn|Ghoche|2012|pp=S2-S3}} Palliative-care specialists can help with physical symptoms, emotional factors such as loss of function and jobs, depression, and fear, as well as existential concerns.{{sfn|Ghoche|2012|p=S3}} Palliative-care team members also help guide difficult decisions caused by disease progression, such as wishes for a [[feeding tube]], [[non-invasive ventilation|noninvasive ventilator]] or [[Tracheotomy|tracheostomy]], use of [[cardiopulmonary resuscitation]], and entering [[hospice]] care.{{sfn|Casey|2013|pp=20–22}}{{sfn|Bernat|Beresford|2013|pp=135, 137, 138}}
== Prognosis ==
{{See also|Unified Parkinson's disease rating scale}}
{| class="wikitable" style="float:right; margin-left:1em; font-size:90%; line-height:1.4em; width:350px;"
|+ Prognosis of PD subtypes{{sfn|Corcoran|Kluger|2023|p=956}}{{sfn|Fereshtehnejad|Zeighami|Dagher|Postuma|2017|p=1967}}
! rowspan="2" style="background:#011E41;color:white;text-align:center;" |Parkinson's subtype
! colspan="2" style="background:#011E41;color:white;text-align:center;" |Mean years post-diagnosis until:
|-
! style="background:#011E41;color:white;" |Severe cognitive or movement abnormalities{{efn|group=note|Defined as the onset of development of recurrent falls, wheelchair dependence, dementia, or facility placement.{{sfn|Corcoran|Kluger|2023|p=956}}}}
! style="background:#011E41;color:white;" |Death
|-
! Mild-motor predominant
|style="text-align:center;"| 14.3
|style="text-align:center;"| 20.2
|-
! Intermediate
|style="text-align:center;"| 8.2
|style="text-align:center;"| 13.1
|-
! Diffuse malignant
|style="text-align:center;"| 3.5
|style="text-align:center;"| 8.1
|-
|}
As PD is a [[heterogeneous condition]] with multiple [[Cause (medicine)|etiologies]], prognostication can be difficult and prognoses can be highly variable.{{sfn|Corcoran|Kluger|2023|p=956}}{{sfn|Tolosa|Garrido|Scholz|Poewe|2021|p=385}} On average, life expectancy is reduced in those with PD, with younger age of onset resulting in greater life expectancy decreases.{{sfn|Dommershuijsen|Darweesh|Ben-Shlomo|Kluger|2023|pp=2–3}} Although PD subtype categorization is controversial, the 2017 Parkinson's Progression Markers Initiative study identified three broad scorable subtypes of increasing severity and more rapid progression - mild-motor predominant, intermediate, and diffuse malignant. Mean years of survival after diagnosis were 20.2, 13.1, and 8.1.{{sfn|Corcoran|Kluger|2023|p=956}}
Around 30% of individuals with PD develop dementia, which is 12 times more likely to occur in the elderly with severe PD.{{sfn|Murueta-Goyena|Muiño|Gómez-Esteban|2017|p=26}} Dementia is less likely to arise in tremor-dominant PD.{{sfn|Murueta-Goyena|Muiño|Gómez-Esteban|2017|p=27}} Parkinson's disease dementia is associated with a reduced [[quality of life]] in people with PD and their [[caregiver]]s, increased mortality, and a higher probability of needing [[nursing home care]].{{sfn|Caballol|Martí|Tolosa|2007|p=S358}}
The incidence rate of falls is around 45 to 68%, three times that of healthy individuals, and half of such falls result in serious secondary injuries. Falls increase [[morbidity]] and [[Mortality rate|mortality]].{{sfn|Murueta-Goyena|Muiño|Gómez-Esteban|2024|p=395}} Around 90% of those with PD develop [[hypokinetic dysarthria]], which worsens with disease progression and can hinder communication.{{sfn|Atalar|Oguz|Genc|2023|p=163}} Over 80% develop dysphagia; consequent inhalation of gastric and oropharyngeal secretions can lead to [[aspiration pneumonia]].{{sfn|Chua|Wang|Chan|Chan|2024|p=1}}
== Epidemiology ==
[[File:Cropduster spraying pesticides.jpg|upright|thumb|Agricultural areas are associated with higher PD [[prevalence]], possibly due to exposure to pesticides and industrial waste.]]
As of 2024, PD is the second-most common neurodegenerative disease and the fastest growing in total cases.{{Sfn|Ben-Shlomo|Darweesh|Llibre-Guerra|Marras|2024|p=283}}{{Sfn|Varden|Walker|O'Callaghan|2024|p=1}} As of 2023, global [[prevalence]] was estimated to be 1.51 per 1000.{{Sfn|Zhu|Cui|Zhang|Yan|2024|p=e464}} Although it is around 40% more common in men,{{Sfn|Ben-Shlomo|Darweesh|Llibre-Guerra|Marras|2024|p=286}} age is the dominant predeterminant of PD.{{Sfn|Deliz|Tanner|Gonzalez-Latapi|2024|p=166}} Consequently, as [[Life expectancy|global life expectancy]] has increased, PD prevalence has also risen, with an estimated increase in cases by 74% from 1990 to 2016.{{Sfn|Ben-Shlomo|Darweesh|Llibre-Guerra|Marras|2024|p=284}} The number is predicted to rise to over 12 million by 2040.{{Sfn|Dorsey|Sherer|Okun|Bloem|2018|p=S4}}
This increase may be due to a number of global factors, including prolonged life expectancy, increased industrialisation, and [[Tobacco control|decreased smoking]].{{Sfn|Ben-Shlomo|Darweesh|Llibre-Guerra|Marras|2024|p=284}} Although genetics is the sole factor in a minority of cases, most cases of PD are likely a result of [[gene-environment interactions]]; [[Concordance (genetics)|concordance studies]] with [[twins]] have found PD [[heritability]] to be just 30%.{{Sfn|Ben-Shlomo|Darweesh|Llibre-Guerra|Marras|2024|p=286}} The influence of multiple genetic and environmental factors complicates epidemiological efforts.{{Sfn|Deliz|Tanner|Gonzalez-Latapi|2024|p=165}}
Relative to Europe and North America, disease prevalence is lower in Africa, but similar in Latin America.{{Sfn|Ben-Shlomo|Darweesh|Llibre-Guerra|Marras|2024|p=285}} Although China is predicted to have nearly half of the global PD population by 2030,{{Sfn|Li|Ma|Cui|He|2019|p=1}} estimates of prevalence in Asia vary.{{Sfn|Ben-Shlomo|Darweesh|Llibre-Guerra|Marras|2024|p=285}} Potential explanations for these geographic differences include genetic variation, environmental factors, [[health care access]], and life expectancy.{{Sfn|Ben-Shlomo|Darweesh|Llibre-Guerra|Marras|2024|p=285}} Although PD incidence and prevalence may vary by race and ethnicity, significant disparities in care, diagnosis, and study participation limit [[generalizability]] and lead to conflicting results.{{Sfn|Ben-Shlomo|Darweesh|Llibre-Guerra|Marras|2024|p=285}}{{Sfn|Deliz|Tanner|Gonzalez-Latapi|2024|p=165}} Within the United States, high rates of PD have been identified in the [[Midwestern United States|Midwest]], the [[Southern United States|South]], and agricultural regions of other states, collectively termed the "PD belt".{{Sfn|Deliz|Tanner|Gonzalez-Latapi|2024|pp=164–165}} The association between rural residence and PD has been hypothesized to be caused by environmental factors including herbicides, pesticides, and industrial waste.{{Sfn|Deliz|Tanner|Gonzalez-Latapi|2024|pp=164–165}}
== History ==
{{Main|History of Parkinson's disease}}
{{Multiple image
| align = right
| total_width = 400
| image1 = Jean-Martin Charcot.jpg
| alt1 = A black and white portrait photograph of Jean-Martin Charcot
| image2 = Photographs of a Parkinson patient Pierre D.jpg
| alt2 = Side and front views of a Parkinson's patient, illustrating hunched posture
| footer = In 1877, [[Jean-Martin Charcot]] (left) named Parkinson's disease after the first person to comprehensively describe it, [[James Parkinson]]. Patient Pierre D. (right) served as the model for [[William Gowers (neurologist)|William Gowers]]' illustration of the disease.{{Sfn|Lewis|Plun-Favreau|Rowley|Spillane|2020|p=389}}}}
In 1817, English physician [[James Parkinson]] published the first full medical description of the disease as a neurological syndrome in his monograph ''An Essay on the Shaking Palsy''.{{Sfn|Goetz|2011|pp=1–2}}{{Sfn|Lees|2007|p=S327}} He presented six clinical cases, including three he had observed on the streets near [[Hoxton Square]] in [[London]].{{Sfn|Goetz|2011|p=2}} Parkinson described three cardinal symptoms: tremor, postural instability, and "paralysis" (undistinguished from rigidity or bradykinesia), and speculated that the disease was caused by trauma to the [[spinal cord]].{{Sfn|Louis|1997|p=1069}}{{Sfn|Lees|2007|p=S328}}
Little discussion of or investigation into the "shaking palsy" occurred until 1861, when Frenchman [[Jean-Martin Charcot]]—regarded as the father of [[neurology]]—began expanding Parkinson's description, adding bradykinesia as one of the four cardinal symptoms.{{Sfn|Louis|1997|p=1069}}{{Sfn|Goetz|2011|p=2}}{{Sfn|Lees|2007|p=S328}} In 1877, Charcot renamed the disease after Parkinson, as the tremor suggested by "shaking palsy" is not present in all.{{Sfn|Goetz|2011|p=2}}{{Sfn|Lees|2007|p=S328}} Subsequent neurologists who made early advances to the understanding of PD include [[Armand Trousseau]], [[William Gowers (neurologist)|William Gowers]], [[Samuel Alexander Kinnier Wilson|Samuel Kinnier Wilson]], and [[Wilhelm Heinrich Erb|Wilhelm Erb]].{{Sfn|Lees|2007|p=S329}}
Although Parkinson is typically credited with the first detailed description of PD, many previous texts reference some of the disease's clinical signs.{{Sfn|Bereczki|2010|p=290}} In his essay, Parkinson himself acknowledged partial descriptions by [[Galen]], [[William Cullen]], [[Johann Juncker]], and others.{{Sfn|Lees|2007|p=S328}} Possible earlier but incomplete descriptions include a [[Nineteenth Dynasty of Egypt|Nineteenth Dynasty]] Egyptian [[papyrus]], the [[ayurvedic]] text ''[[Charaka Samhita]]'', [[Ecclesiastes 12|Ecclesiastes 12:3]], and a discussion of tremors by [[Leonardo da Vinci]].{{Sfn|Lees|2007|p=S328}}{{Sfn|Blonder|2018|pp=3–4}} Multiple [[traditional Chinese medicine]] texts may include references to PD, including a discussion in the [[Yellow Emperor]]'s Internal Classic ({{Circa|425–221 BC}}) of a disease with symptoms of tremor, stiffness, staring, and stooped posture.{{Sfn|Blonder|2018|pp=3–4}} In 2009, a systematic description of PD was found in the Hungarian medical text ''Pax corporis'' written by Ferenc Pápai Páriz in 1690, some 120 years before Parkinson. Although Páriz correctly described all four cardinal signs, it was only published in Hungarian and was not widely distributed.{{Sfn|Bereczki|2010|pp=290–293}}{{Sfn|Blonder|2018|p=3}}
In 1912, [[Frederic Lewy]] described microscopic particles in affected brains, later named Lewy bodies.{{Sfn|Sousa-Santos|Pozzobon|Teixeira|2024|pp=1–2}} In 1919, [[Konstantin Tretiakoff]] reported that the substantia nigra was the main brain structure affected, corroborated by [[Rolf Hassler]] in 1938.{{Sfn|Lees|2007|p=S331}} The underlying changes in dopamine signaling were identified in the 1950s, largely by [[Arvid Carlsson]] and [[Oleh Hornykiewicz]].{{Sfn|Fahn|2008|p=S500–S501, S504–S505}} In 1997, [[Mihael Polymeropoulos|Polymeropoulos]] and colleagues at the [[National Institutes of Health|NIH]] discovered the first gene for PD,{{sfn|Polymeropoulos|Lavedan|Leroy|Ide|1997}} ''SNCA'', which encodes alpha-synuclein. Alpha-synuclein was, in turn, found to be the main component of Lewy bodies by [[Maria Grazia Spillantini|Spillantini]], [[John Q. Trojanowski|Trojanowski]], [[Michel Goedert|Goedert]], and others.{{Sfn|Schulz-Schaeffer|2010|p=131}} Anticholinergics and surgery were the only treatments until the use of levodopa,{{Sfn|Lanska|2010|p=507}}{{Sfn|Guridi|Lozano|1997|pp=1180–1183}} which, although first synthesized by [[Casimir Funk]] in 1911,{{Sfn|Fahn|2008|p=S497}} did not enter clinical use until 1967.{{Sfn|Fahn|2008|p=S501}} By the late 1980s, deep brain stimulation introduced by [[Alim Louis Benabid]] and colleagues at [[Grenoble]], France, emerged as an additional treatment.{{Sfn|Coffey|2009|pp=209–210}}
== Society and culture ==
=== Social impact ===
[[File:Drawing of face of parkinsons disease patient showing hypomimia.jpg|thumb|alt=A sketch showing hypomimia, a blank, expressionless face|upright=0.7|The [[Hypomimia|reduced ability to facially express emotions]]—as depicted here by French anatomist [[Paul Richer]] in 1888—can harm social well-being.]]
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.{{sfn|Prenger|Madray|Van Hedger|Anello|2020|p=2}} As the condition progresses, tremor, other motor symptoms, difficulty communicating, or mobility issues may interfere with social engagement, causing individuals with PD to feel isolated.{{sfn|Crooks|Carter|Wilson|Wynne|2023|p=2,7}} 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.{{sfn|Crooks|Carter|Wilson|Wynne|2023|p=2}}
=== Cost ===
The economic cost of Parkinson's to both individuals and society is high.{{sfn|Schiess|Cataldi|Okun|Fothergill-Misbah|2022|p=931}} In many low- and middle-income countries, public health systems may not fully cover Parkinson’s disease therapies, leading to disparities in access to treatment. In contrast, high-income countries with universal healthcare typically cover standard treatments such as levodopa and specialist care. {{sfn|Schiess|Cataldi|Okun|Fothergill-Misbah|2022|p=931}} Indirect costs include lifetime earnings losses due to premature death, productivity losses, and caregiver burdens.{{sfn|Yang|Hamilton|Kopil|Beck|2020|p=1}} The duration and progressive nature of PD can place a heavy burden on caregivers;{{sfn|Schiess|Cataldi|Okun|Fothergill-Misbah|2022|p=933}} family members, such as spouses, dedicate around 22 hours per week to care.{{sfn|Yang|Hamilton|Kopil|Beck|2020|p=1}}
In 2010, the total economic burden of PD across Europe, including indirect and direct medical costs, was estimated to be €13.9 billion (US $14.9 billion).{{sfn|Schiess|Cataldi|Okun|Fothergill-Misbah|2022|p=929}} The total burden in the United States was estimated to be $51.9 billion in 2017, and is projected to surpass $79 billion by 2037.{{sfn|Yang|Hamilton|Kopil|Beck|2020|p=1}} As of 2022, no rigorous economic surveys had been performed for low- or middle-income nations.{{sfn|Schiess|Cataldi|Okun|Fothergill-Misbah|2022|p=930}} Preventive care has been identified as crucial to slow the rapidly increasing incidence of Parkinson's from overwhelming national health systems.{{sfn|Schiess|Cataldi|Okun|Fothergill-Misbah|2022|p=933}}
===
The birthday of James Parkinson, 11 April, has been designated as World Parkinson's Day.{{sfn|Lees|2007|pages=S327–S334}} 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.{{sfn|GlaxoSmithKline}}
Advocacy organizations include the [[National Parkinson Foundation]], which has provided more than $180 million in care, research, and support services since 1982,{{sfn|National Parkinson Foundation}} [[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;{{sfn|Time 1960}}{{sfn|Parkinson's Disease Foundation}} the [[American Parkinson Disease Association]], founded in 1961;{{sfn|American Parkinson Disease Association}} and the European Parkinson's Disease Association, founded in 1992.{{sfn|European Parkinson's Disease Association}}
=== Notable cases ===
{{Main|List of people diagnosed with Parkinson's disease}}<!--
BEFORE ADDING INDIVIDUALS, please review [[WP:MEDCASE] regarding individuals who have made a lasting impression on the condition ... others can be added to the List subarticle
-->[[File:0522 ma big cropped.png|thumb|alt=Michael J. Fox and Muhammad Ali are seen speaking to reporters, with the marble walls of the U.S. Senate behind them|Actor [[Michael J. Fox]] and boxer [[Muhammad Ali]] (center) are pictured in 2002 speaking before the [[US Senate]] to urge increased funding for Parkinson's research.]]
In the 21st century, the diagnosis of PD among notable figures has increased the public's understanding of the disorder.{{sfn|Parkinson's Foundation}} Actor [[Michael J. Fox]] was diagnosed with PD at 29 years old,{{sfn|The Michael J. Fox Foundation for Parkinson's Research}} and has used his diagnosis to increase awareness of the disease.{{sfn|Davis|2007}} To illustrate the effects of the disease, Fox has appeared without medication in television roles and before the [[United States Congress]].{{sfn|Brockes|2009}} [[The Michael J. Fox Foundation]], which he founded in 2000, has raised over $2 billion for Parkinson's research.{{sfn|Burleson|Breen|2023}}
Boxer [[Muhammad Ali]] showed signs of PD when he was 38, but was undiagnosed until he was 42; he has been called the "world's most famous Parkinson's patient".
{{sfn|Brey|2006}} Whether he had PD or [[Dementia pugilistica|parkinsonism related to boxing]] is unresolved.{{sfn|Matthews|2006|p=10–23}} Cyclist and Olympic medalist [[Davis Phinney]], diagnosed with PD at 40, started the [[Davis Phinney Foundation]] in 2004 to support PD research.{{sfn|Macur|2008}}{{sfn|Davis Phinney Foundation}}
Musician [[Ozzy Osbourne]] was diagnosed with PD; he performed a July 5, 2025, farewell reunion concert with the band he co-founded, [[Black Sabbath]], weeks before his death. The event raised over $190 million, some of which went to Parkinson's disease research.<ref>{{cite magazine | title=Ozzy Osbourne, Black Sabbath Singer and Heavy Metal Pioneer, Dead at 76 | magazine=[[Rolling Stone]] | url=https://www.rollingstone.com/music/music-news/ozzy-osbourne-black-sabbath-dead-obituary-1227265/ }}</ref>
[[Adolf Hitler]] is believed to have had PD, and the condition may have influenced his decision-making.{{sfn|Gupta|Kim|Agarwal|Lieber|2015|pp=1447–1452}}{{sfn|Boettcher|Bonney|Smitherman|Sughrue|2015|p=E8}}{{sfn|Lieberman|1996|p=95}}
== Clinical research ==
{{Main|Research in Parkinson's disease}}
[[File:ISS-57 Alexander Gerst works in the Harmony module (1).jpg|thumb|alt=A European astronaut is seen in zero gravity conducting research with a micropipette|Astronaut [[Alexander Gerst]] conducted PD research aboard the [[International Space Station]] in 2018.]]
As of 2024, no disease-modifying therapies exist that reverse or slow the progression of PD.{{Sfn|Crotty|Schwarzschild|2020|p=1}}{{Sfn|Fabbri|Rascol|Foltynie|Carroll|2024|p=2}} Active research directions include the search for new [[animal model]]s of the disease and development and trial of [[gene therapy]], [[stem cell]] transplants, and [[neuroprotective]] agents.{{sfn|Poewe|Seppi|Tanner|Halliday|2017}} Improved treatments will likely combine therapeutic strategies to manage symptoms and enhance outcomes.{{sfn|Pardo-Moreno|García-Morales|Suleiman-Martos|Rivas-Domínguez|2023|p=1}} Reliable [[biomarker (medicine)|biomarkers]] are needed for early diagnosis, and research criteria for their identification have been established.{{sfn|Li|Le|2020|p=183}}{{sfn|Heinzel|Berg|Gasser|Chen|2019}}
=== Neuroprotective treatments ===
{{See also|Anti-α-synuclein drug}}
[[Anti-alpha-synuclein drugs|Drugs that prevent alpha-synuclein]] oligomerization and aggregation or promote their clearance are under active investigation, and potential therapeutic strategies include [[small molecules]] and [[immunotherapies]] including [[vaccines]] and [[monoclonal antibodies]].{{sfn|Pardo-Moreno|García-Morales|Suleiman-Martos|Rivas-Domínguez|2023|pp=12–13}}{{sfn|Alfaidi|Barker|Kuan|2024|p=1}}{{sfn|Jasutkar|Oh|Mouradian|2022|p=208}} While immunotherapies show promise, their efficacy is often inconsistent.{{sfn|Alfaidi|Barker|Kuan|2024|p=1}} Anti-inflammatory drugs that target [[NLRP3]] and the [[JAK-STAT signaling pathway]] offer another potential therapeutic approach.{{sfn|Pardo-Moreno|García-Morales|Suleiman-Martos|Rivas-Domínguez|2023|pp=10–11}}
As the [[gut microbiome]] in PD is often disrupted and produces toxic compounds, [[fecal microbiota transplants]] might restore a healthy microbiome and alleviate various motor and non-motor symptoms.{{sfn|Pardo-Moreno|García-Morales|Suleiman-Martos|Rivas-Domínguez|2023|pp=12–13}} [[Neurotrophic factors]]—[[peptides]] that enhance the growth, maturation, and survival of neurons—show modest results, but require invasive surgical administration. [[Viral vectors]] may represent a more feasible delivery platform.{{sfn|Pardo-Moreno|García-Morales|Suleiman-Martos|Rivas-Domínguez|2023|p=13}} Calcium channel blockers may restore the calcium imbalance present in PD, and are being investigated as a neuroprotective treatment.{{sfn|Pardo-Moreno|García-Morales|Suleiman-Martos|Rivas-Domínguez|2023|p=10}} Other therapies, such as [[deferiprone]], may reduce the abnormal accumulation of iron in PD.{{sfn|Pardo-Moreno|García-Morales|Suleiman-Martos|Rivas-Domínguez|2023|p=10}}
=== Cell-based therapies ===
{{Main|Cell-based therapies for Parkinson's disease}}
{{Multiple image
| align = right
| total_width = 400
| image1 = Parkinson's induced pluripotent stem cell.jpg
| alt1 = Researchers at Argonne National Laboratory examining a culture of induced pluripotent stem cells
| image2 = Efficient-Conversion-of-Astrocytes-to-Functional-Midbrain-Dopaminergic-Neurons-Using-a-Single-pone.0028719.s002.ogv
| alt2 = The action potentials of an astrocyte converted into a dopaminergic neuron
| footer = Researchers at [[Argonne National Laboratory]] examine [[induced pluripotent stem cells]] (iPSCs) for use in Parkinson's and other diseases: the [[action potentials]] of one such iPSC differentiated into a [[dopaminergic neuron]] are visible at right.
}}
In contrast to other neurodegenerative disorders, many PD symptoms can be attributed to the loss of a single cell type. Consequently, dopaminergic neuron regeneration is a promising therapeutic approach.{{Sfn|Parmar|Grealish|Henchcliffe|2020|pp=103}} Although most initial research sought to generate dopaminergic neuron precursor cells from fetal brain tissue,{{Sfn|Parmar|Grealish|Henchcliffe|2020|pp=103–104}} [[Pluripotency|pluripotent stem cells]]—particularly [[induced pluripotent stem cells]] (iPSC)—have become an increasingly popular tissue source.{{Sfn|Parmar|Grealish|Henchcliffe|2020|pp=106}}{{Sfn|Henchcliffe|Parmar|2018|pp=134}}
Both fetal and iPSC-derived DA neurons have been transplanted into patients in clinical trials.{{Sfn|Parmar|Grealish|Henchcliffe|2020|pp=106, 108}}{{sfn|Schweitzer|Song|Herrington|Park|2020|p=1926}} Although some individuals have seen improvement, the results are highly variable. Adverse effects, such as [[Tardive dyskinesia|dyskinesia]] arising from excess dopamine release by the transplanted tissues, have also been observed.{{Sfn|Parmar|Grealish|Henchcliffe|2020|pp=105, 109}}{{Sfn|Henchcliffe|Parmar|2018|pp=132}}
===
{{Main|Gene therapy in Parkinson's disease}}
[[Gene therapy]] for PD seeks to restore the healthy function of dopaminergic neurons in the substantia nigra by delivering genetic material—typically through a viral vector—to these diseased cells.{{sfn|Van Laar|Van Laar|San Sebastian|Merola|2021|p=S174}}{{sfn|Hitti|Yang|Gonzalez-Alegre|Baltuch|2019|p=16}} This material may deliver a functional, [[Wild type|wild-type]] version of a gene, or [[Gene knockdown|knock down]] a pathological variant.{{sfn|Hitti|Yang|Gonzalez-Alegre|Baltuch|2019|pp=16–17}} Experimental gene therapies for PD have aimed to increase the expression of [[growth factors]] or enzymes involved in dopamine synthesis, such as [[tyrosine hydroxylase]].{{sfn|Van Laar|Van Laar|San Sebastian|Merola|2021|p=S174, S176}} The one-time delivery of genes circumvents the recurrent invasive administration required to administer some peptides and proteins to the brain.{{sfn|Hitti|Yang|Gonzalez-Alegre|Baltuch|2019|p=21}} MicroRNAs are an emerging PD gene therapy platform that may serve as an alternative to viral vectors.{{sfn|Shaheen|Shaheen|Osama|Nashwan|2024|pp=5–6}}
== See also ==
*[[NLRP3 inflammasome]]
*[[Neuroinflammation]]
*[[Selnoflast]]
*[[Innate immune system]]
*[[Interleukin-1β]]
*[[Caspase-1]]
== Notes and references ==
===
{{reflist|group=note}}
{{Reflist|colwidth=20em}}
=== Works cited ===
==== Books ====
{{Refbegin|20em}}
* {{Cite book |title=Parkinson's Disease |vauthors=Bhattacharyya KB |date=2017 |publisher=International Review of Neurobiology |veditors=Bhatia KP, Chaudhuri KR, Stamelou M |pages=1–23 |chapter=Chapter One – Hallmarks of Clinical Aspects of Parkinson's Disease Through Centuries}}
* {{cite book |last1=Bernat |first1=James L. |last2=Beresford |first2=Richard |title=Ethical and Legal Issues in Neurology |date=2013 |publisher=Newnes |isbn=978-0-444-53504-7 |url=https://books.google.com/books?id=YTY3AAAAQBAJ |language=en}}
* {{Cite book |title=Ferri's differential diagnosis: a practical guide to the differential diagnosis of symptoms, signs, and clinical disorders |vauthors=Ferri FF |date=2010 |publisher=Elsevier/Mosby |isbn=978-0-3230-7699-9 |edition=2nd |chapter=Chapter P}}
* {{Cite book |title=Handbook of Clinical Neurology |vauthors=Lanska DJ |date=2010 |publisher=History of Neurology |series=3 |volume=95 |pages=501–546 |chapter=Chapter 33: The history of movement disorders |doi=10.1016/S0072-9752(08)02133-7 |pmid=19892136|isbn=978-0-444-52009-8 }}
* {{Cite book |title=Physical Rehabilitation |vauthors=O'Sullivan SB, Schmitz TJ |publisher=F.A. Davis |year=2007 |isbn=978-0-8036-1247-1 |edition=5th |chapter=Parkinson's Disease}}
* {{Cite book |title=Lange Clinical Neurology |vauthors=Simon RP, Greenberg D, Aminoff MJ |publisher=McGraw-Hill |year=2017 |isbn=978-1-2598-6172-7 |edition=10th}}
* {{Cite book |url=https://exonpublications.com/index.php/exon/issue/view/9 |title=Parkinson's Disease: Pathogenesis and Clinical Aspects |date=December 2018 |publisher=Codon Publications |isbn=978-0-9944-3816-4 |veditors=Stoker TB, Greenland JC |ref=none}}
** {{Cite book |title=Parkinson's disease: Pathogenesis and Clinical Aspects |vauthors=Greenland JC, Barker RA |date=2018 |publisher=Codon Publications |isbn=978-0-9944-3816-4 |veditors=Stoker TB, Greenland JC |pages=109–128 |chapter=Chapter 6: The Differential Diagnosis of Parkinson's Disease |doi=10.15586/codonpublications.parkinsonsdisease.2018.ch6 |pmid=30702839 |chapter-url=https://exonpublications.com/index.php/exon/article/view/191/348 |s2cid=80908095}}
*{{Cite book |title=Parkinson's Disease |publisher=Royal College of Physicians |year=2006 |isbn=978-1-8601-6283-1 |editor-last=The National Collaborating Centre for Chronic Conditions |___location=London |pages=113–133 |chapter=Non-motor features of Parkinson's disease |chapter-url=http://guidance.nice.org.uk/CG35/Guidance/pdf/English |archive-url=https://web.archive.org/web/20100924153546/http://guidance.nice.org.uk/CG35/Guidance/pdf/English |archive-date=24 September 2010 |url-status=live|ref={{Harvid|The National Collaborating Centre for Chronic Conditions}}}}
{{Refend}}
==== Journal articles ====
{{Refbegin|20em}}
*{{Cite journal|vauthors=Aarslanda D, Krambergera MG|date=2015|title=Neuropsychiatric Symptoms in Parkinson's Disease|journal=Journal of Personalized Medicine |volume=5|issue=3 |pages=659–667|doi=10.3233/JPD-150604 |pmid=26406147}}
*{{Cite journal |vauthors=Abusrair AH, Elsekaily W, Bohlega S |date=13 September 2022 |title=Tremor in Parkinson's Disease: From Pathophysiology to Advanced Therapies |journal=Tremor and Other Hyperkinetic Movements |volume=12 |issue=1 |article-number=29 |doi=10.5334/tohm.712 |pmc=9504742 |pmid=36211804 |doi-access=free}}
*{{Cite journal |vauthors=Ahlskog JE |date=July 2011 |title=Does vigorous exercise have a neuroprotective effect in Parkinson disease? |journal=Neurology |volume=77 |issue=3 |pages=288–294 |doi=10.1212/wnl.0b013e318225ab66 |pmc=3136051 |pmid=21768599}}
*{{Cite journal|vauthors=Alfaidi M, Barker RA, Kuan W|date=2024|title=An update on immune-based alpha-synuclein trials in Parkinson's disease|journal=Journal of Neurology|volume=272 |issue=1|article-number=21 |doi=10.1007/s00415-024-12770-x |pmid= 39666171|pmc=11638298 }}
*{{Cite journal |vauthors=Almikhlafi MA |date=January 2024 |title=A review of the gastrointestinal, olfactory, and skin abnormalities in patients with Parkinson's disease |journal=Neurosciences |volume=29 |issue=1 |pages=4–9 |doi=10.17712/nsj.2024.1.20230062 |doi-broken-date=12 July 2025 |pmc=10827020 |pmid=38195133}}
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{{Refend}}
==== Web sources ====
{{Refbegin|20em}}
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*{{Cite web |date=1 April 2009 |title=Parkinson's – 'the shaking palsy' |url=http://www.gsk.com/infocus/parkinsons.htm |archive-url=https://web.archive.org/web/20110514151652/http://www.gsk.com/infocus/parkinsons.htm |archive-date=14 May 2011 |publisher=GlaxoSmithKline|ref={{Harvid|GlaxoSmithKline}}}}
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{{Refend}}
====
{{Refbegin}}
*{{cite news|url=https://www.theguardian.com/lifeandstyle/2009/apr/11/michael-j-fox-parkinsons|title='It's the gift that keeps on taking'|date=11 April 2009| vauthors = Brockes E |work=The Guardian|access-date=25 October 2010|url-status=live|archive-url=https://web.archive.org/web/20131008000425/http://www.theguardian.com/lifeandstyle/2009/apr/11/michael-j-fox-parkinsons|archive-date=8 October 2013}}
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*{{cite news| url= http://www.time.com/time/specials/2007/time100/article/0,28804,1595326_1615754_1615882,00.html| title=Michael J. Fox| date=3 May 2007| vauthors = Davis P| work=The Time 100| publisher=[[Time (magazine)|Time]] |___location=New York |access-date=2 April 2011 |archive-url= https://web.archive.org/web/20110425013526/http://www.time.com/time/specials/2007/time100/article/0,28804,1595326_1615754_1615882,00.html| archive-date=25 April 2011 }}
*{{Cite magazine |date=18 January 1960 |title=Education: Joy in Giving |url=http://www.time.com/time/magazine/article/0,9171,828597,00.html |archive-url=https://web.archive.org/web/20110220012106/http://www.time.com/time/magazine/article/0,9171,828597,00.html |archive-date=20 February 2011 |access-date=2 April 2011 |magazine=Time|ref={{Harvid|Time 1960}}}}
{{Refend}}
{{sisterlinks|d=Q11085|c=Category:Parkinson's disease|n=no|b=no|v=no|voy=no|m=no|mw=no|s=no|wikt=no|species=no}}
{{Medical condition classification and resources
| DiseasesDB = 9651
| ICD11 = {{ICD11|8A00.0}}
| ICD10 = {{ICD10|G20}}, {{ICD10|F02.3}}
| ICD9 = {{ICD9|332}}
| ICDO =
| OMIM = 168600
| OMIM_mult = {{OMIM|556500||none}}
| MedlinePlus = 000755
| eMedicineSubj = neuro
| eMedicineTopic = 304
| eMedicine_mult = {{EMedicine2|neuro|635}} in young<br/>{{EMedicine2|pmr|99}} rehab
|MeSH=D010300
| GeneReviewsNBK = NBK1223
| GeneReviewsName = Parkinson Disease Overview
}}
{{Antiparkinson}}
{{CNS diseases of the nervous system}}
{{Mental and behavioral disorders|selected=neurological}}
[[Category:Parkinson's disease|Parkinson's disease]]
[[Category:Aging-associated diseases]]
[[Category:Ailments of unknown cause]]
[[Category:Articles containing video clips]]
[[Category:Cytoskeletal defects]]
[[Category:Diseases named after discoverers]]
[[Category:Geriatrics]]
[[Category:
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Wikipedia neurology articles ready to translate]]
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