World Library  
Flag as Inappropriate
Email this Article

Parkinson's disease

Article Id: WHEBN0022228064
Reproduction Date:

Title: Parkinson's disease  
Author: World Heritage Encyclopedia
Language: English
Subject: Dopamine agonist, Dopamine, Placebo, Tremor, HollyRod Foundation
Collection: Aging-Associated Diseases, Cytoskeletal Defects, Geriatrics, Parkinson's Disease, Psychiatric Diagnosis
Publisher: World Heritage Encyclopedia

Parkinson's disease

Parkinson's disease
Classification and external resources
Two sketches (one from the front and one from the right side) of a man, with an expressionless face. He is stooped forward and is presumably having difficulty walking.
Illustration of Parkinson's disease by William Richard Gowers, which was first published in A Manual of Diseases of the Nervous System (1886)
ICD-10 G20, F02.3
ICD-9 332
OMIM 168600 556500
DiseasesDB 9651
MedlinePlus 000755
eMedicine neuro/304 neuro/635 in young
pmr/99 rehab
  • Parkinson Disease Overview

Parkinson's disease (PD, also known as idiopathic or primary parkinsonism, hypokinetic rigid syndrome/HRS, or paralysis agitans) is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown. Early in the course of the disease, the most obvious symptoms are movement-related; these include shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, whereas depression is the most common psychiatric symptom. Other symptoms include sensory, sleep and emotional problems. Parkinson's disease is more common in older people, with most cases occurring after the age of 50.

The main motor symptoms are collectively called parkinsonism, or a "parkinsonian syndrome". Parkinson's disease is often defined as a parkinsonian syndrome that is idiopathic (having no known cause), although some atypical cases have a genetic origin. Many risk and protective factors have been investigated: the clearest evidence is for an increased risk of PD in people exposed to certain pesticides and a reduced risk in tobacco smokers. The pathology of the disease is characterized by the accumulation of a protein called alpha-synuclein into inclusions called Lewy bodies in neurons, and from insufficient formation and activity of dopamine produced in certain neurons within parts of the midbrain. Lewy bodies are the pathological hallmark of the idiopathic disorder, and the distribution of the Lewy bodies throughout the Parkinsonian brain varies from one individual to another. The anatomical distribution of the Lewy bodies is often directly related to the expression and degree of the clinical symptoms of each individual. Diagnosis of typical cases is mainly based on symptoms, with tests such as neuroimaging being used for confirmation.

Modern treatments are effective at managing the early motor symptoms of the disease, mainly through the use of levodopa and dopamine agonists. As the disease progresses and dopaminergic neurons continue to be lost, these drugs eventually become ineffective at treating the symptoms and at the same time produce a complication called dyskinesia, marked by involuntary writhing movements. Diet and some forms of rehabilitation have shown some effectiveness at alleviating symptoms. Surgery and deep brain stimulation have been used to reduce motor symptoms as a last resort in severe cases where drugs are ineffective. Research directions include investigations into new animal models of the disease and of the potential usefulness of gene therapy, stem cell transplants and neuroprotective agents. Medications to treat non-movement-related symptoms of PD, such as sleep disturbances and emotional problems, also exist.

The disease is named after the English doctor actor Michael J. Fox, Olympic cyclist Davis Phinney, and professional boxer Muhammad Ali. Parkinson's not only affects humans, but other primates as well, which have often been used in researching the disease and testing approaches to its treatment.[2][3][4]


  • Classification 1
  • Signs and symptoms 2
    • Motor 2.1
    • Neuropsychiatric 2.2
    • Other 2.3
  • Causes 3
    • Environmental factors 3.1
    • Genetics 3.2
  • Pathology 4
    • Anatomical 4.1
    • Pathophysiology 4.2
    • Brain cell death 4.3
  • Diagnosis 5
  • Prevention 6
  • Management 7
    • Levodopa 7.1
    • Dopamine agonists 7.2
    • MAO-B inhibitors 7.3
    • Other drugs 7.4
    • Surgery 7.5
    • Rehabilitation 7.6
    • Palliative care 7.7
    • Other treatments 7.8
  • Prognosis 8
  • Epidemiology 9
  • History 10
  • Society and culture 11
    • Cost 11.1
    • Advocacy 11.2
    • Notable cases 11.3
  • Research 12
    • Animal models 12.1
    • Gene therapy 12.2
    • Neuroprotective treatments 12.3
    • Neural transplantation 12.4
  • References 13
  • External links 14


The term parkinsonism is used for a motor syndrome whose main symptoms are tremor at rest, stiffness, slowing of movement and postural instability. Parkinsonian syndromes can be divided into four subtypes according to their origin:

  1. primary or idiopathic
  2. secondary or acquired
  3. hereditary parkinsonism, and
  4. Parkinson plus syndromes or multiple system degeneration.[5]

Parkinson's disease is the most common form of parkinsonism and is usually defined as "primary" parkinsonism, meaning parkinsonism with no external identifiable cause.[6][7] In recent years several genes that are directly related to some cases of Parkinson's disease have been discovered. As much as this conflicts with the definition of Parkinson's disease as an idiopathic illness, genetic parkinsonism disorders with a similar clinical course to PD are generally included under the Parkinson's disease label. The terms "familial Parkinson's disease" and "sporadic Parkinson's disease" can be used to differentiate genetic from truly idiopathic forms of the disease.[8]

Usually classified as a movement disorder, PD also gives rise to several non-motor types of symptoms such as sensory deficits,[9] cognitive difficulties or sleep problems. Parkinson plus diseases are primary parkinsonisms which present additional features.[6] They include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy bodies.[6][10]

In terms of pathophysiology, PD is considered a synucleiopathy due to an abnormal accumulation of alpha-synuclein protein in the brain in the form of Lewy bodies, as opposed to other diseases such as Alzheimer's disease where the brain accumulates tau protein in the form of neurofibrillary tangles.[11] Nevertheless, there is clinical and pathological overlap between tauopathies and synucleinopathies. The most typical symptom of Alzheimer's disease, dementia, occurs in advanced stages of PD, while it is common to find neurofibrillary tangles in brains affected by PD.[11]

Dementia with Lewy bodies (DLB) is another synucleinopathy that has similarities with PD, and especially with the subset of PD cases with dementia. However the relationship between PD and DLB is complex and still has to be clarified.[12] They may represent parts of a continuum or they may be separate diseases.[12]

Signs and symptoms

Black and white picture of male with PD stooping forward as he walks. He is viewed from the left side and there is a chair behind him.
A man with Parkinson's disease displaying a flexed walking posture pictured in 1892. Photo appeared in Nouvelle Iconographie de la Salpètrière, vol. 5.

First line of text is
Handwriting of a person affected by PD in Lectures on the diseases of the nervous system by Charcot (1879). The original description of the text states "The strokes forming the letters are very irregular and sinuous, whilst the irregularities and sinuosities are of a very limited width. (...) the down-strokes are all, with the exception of the first letter, made with comparative firmness and are, in fact, nearly normal — the finer up-strokes, on the contrary, are all tremulous in appearance (...)."

Parkinson's disease affects movement, producing motor symptoms.[5] Non-motor symptoms, which include autonomic dysfunction, neuropsychiatric problems (mood, cognition, behavior or thought alterations), and sensory and sleep difficulties, are also common. Some of these non-motor symptoms are often present at the time of diagnosis and can precede motor symptoms.[5]


Four motor symptoms are considered cardinal in PD: tremor, rigidity, slowness of movement, and postural instability.[5]

Tremor is the most apparent and well-known symptom.[5] It is the most common; though around 30% of individuals with PD do not have tremor at disease onset, most develop it as the disease progresses.[5] It is usually a rest tremor: maximal when the limb is at rest and disappearing with voluntary movement and sleep.[5] It affects to a greater extent the most distal part of the limb and at onset typically appears in only a single arm or leg, becoming bilateral later.[5] Frequency of PD tremor is between 4 and 6 hertz (cycles per second). A feature of tremor is pill-rolling, the tendency of the index finger of the hand to get into contact with the thumb and perform together a circular movement.[5][13] The term derives from the similarity between the movement in people with PD and the earlier pharmaceutical technique of manually making pills.[13]

Bradykinesia (slowness of movement) is another characteristic feature of PD, and is associated with difficulties along the whole course of the movement process, from planning to initiation and finally execution of a movement.[5] Performance of sequential and simultaneous movement is hindered.[5] Bradykinesia is commonly a very disabling symptom in the early stages of the disease.[6] Initial manifestations are problems when performing daily tasks which require fine motor control such as writing, sewing or getting dressed.[5] Clinical evaluation is based in similar tasks such as alternating movements between both hands or both feet.[6] Bradykinesia is not equal for all movements or times. It is modified by the activity or emotional state of the subject, to the point that some people are barely able to walk yet can still ride a bicycle.[5] Generally people with PD have less difficulty when some sort of external cue is provided.[5][14]

Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, an excessive and continuous contraction of muscles.[5] In parkinsonism the rigidity can be uniform (lead-pipe rigidity) or ratchety (cogwheel rigidity).[5][6][15][16] The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity.[17] Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease.[5] In early stages of Parkinson's disease, rigidity is often asymmetrical and it tends to affect the neck and shoulder muscles prior to the muscles of the face and extremities.[18] With the progression of the disease, rigidity typically affects the whole body and reduces the ability to move.

Postural instability is typical in the late stages of the disease, leading to impaired balance and frequent falls,[19] and secondarily to bone fractures.[5] Instability is often absent in the initial stages, especially in younger people.[6] Up to 40% may experience falls and around 10% may have falls weekly, with number of falls being related to the severity of PD.[5]

Other recognized motor signs and symptoms include gait and posture disturbances such as festination (rapid shuffling steps and a forward-flexed posture when walking),[5] speech and swallowing disturbances including voice disorders,[20] mask-like face expression or small handwriting, although the range of possible motor problems that can appear is large.[5]


Parkinson's disease can cause neuropsychiatric disturbances which can range from mild to severe. This includes disorders of speech, cognition, mood, behaviour, and thought.[5]

Cognitive disturbances can occur in the initial stages of the disease and sometimes prior to diagnosis, and increase in prevalence with duration of the disease.[5][21] The most common cognitive deficit in affected individuals is executive dysfunction, which can include problems with planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information. Fluctuations in attention and slowed cognitive speed are among other cognitive difficulties. Memory is affected, specifically in recalling learned information. Nevertheless, improvement appears when recall is aided by cues. Visuospatial difficulties are also part of the disease, seen for example when the individual is asked to perform tests of facial recognition and perception of the orientation of drawn lines.[21]

A person with PD has two to six times the risk of dementia compared to the general population.[5][21] The prevalence of dementia increases with duration of the disease.[21] Dementia is associated with a reduced quality of life in people with PD and their caregivers, increased mortality, and a higher probability of needing nursing home care.[21]

Behavior and mood alterations are more common in PD without cognitive impairment than in the general population, and are usually present in PD with dementia. The most frequent mood difficulties are depression, apathy and anxiety.[5] Establishing the diagnosis of depression is complicated by symptoms that often occur in Parkinson's including dementia, decreased facial expression, decreased movement, a state of indifference, and quiet speech.[22] Impulse control behaviors such as medication overuse and craving, binge eating, hypersexuality, or pathological gambling can appear in PD and have been related to the medications used to manage the disease.[5][23] Psychotic symptoms—hallucinations or delusions—occur in 4% of people with PD, and it is assumed that the main precipitant of psychotic phenomena in Parkinson’s disease is dopaminergic excess secondary to treatment; it therefore becomes more common with increasing age and levodopa intake.[24][25]


In addition to cognitive and motor symptoms, PD can impair other body functions. Sleep problems are a feature of the disease and can be worsened by medications.[5] Symptoms can manifest as daytime drowsiness, disturbances in REM sleep, or insomnia.[5] Alterations in the autonomic nervous system can lead to orthostatic hypotension (low blood pressure upon standing), oily skin and excessive sweating, urinary incontinence and altered sexual function.[5] Constipation and gastric dysmotility can be severe enough to cause discomfort and even endanger health.[26] PD is related to several eye and vision abnormalities such as decreased blink rate, dry eyes, deficient ocular pursuit (eye tracking) and saccadic movements (fast automatic movements of both eyes in the same direction), difficulties in directing gaze upward, and blurred or double vision.[5][27] Changes in perception may include an impaired sense of smell, sensation of pain and paresthesia (skin tingling and numbness).[5] All of these symptoms can occur years before diagnosis of the disease.[5]


Parkinson's disease in most people is idiopathic (having no specific known cause). However, a small proportion of cases can be attributed to known genetic factors. Other factors have been associated with the risk of developing PD, but no causal relationships have been proven.

Environmental factors

U.S. Army helicopter spraying Agent Orange over Vietnamese agricultural land during the Vietnam war.

A number of environmental factors have been associated with an increased risk of Parkinson's including: pesticide exposure, head injuries, and living in the country or farming.[28][29] Rural environments and the drinking of well water may be risks as they are indirect measures of exposure to pesticides.[30][31]

Implicated agents include

  • Parkinson's Disease at DMOZ
  • Parkinson's Disease: Hope Through Research (National Institute of Neurological Disorders and Stroke)
  • World Parkinson Disease Association
  • PDGENE – Database for Parkinson's Disease genetic association studies

External links

  1. ^ Shulman, JM; De Jager, PL; Feany, MB (February 2011) [October 25, 2010]. "Parkinson's disease: genetics and pathogenesis.". Annual review of pathology 6: 193–222.  
  2. ^
  3. ^
  4. ^ Pereira, EA; Aziz, TZ (May 2006). "Parkinson's disease and primate research: past, present, and future".  
  5. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am Jankovic, J (April 2008). "Parkinson's disease: clinical features and diagnosis".  
  6. ^ a b c d e f g h i j k l m n Samii, A; Nutt, JG; Ransom, BR (29 May 2004). "Parkinson's disease".  
  7. ^ Schrag, A (2007). "Epidemiology of movement disorders". In Tolosa, E; Jankovic, JJ. Parkinson's disease and movement disorders. Hagerstown, Maryland: Lippincott Williams & Wilkins. pp. 50–66.  
  8. ^ a b c d e f g h Davie CA (2008). "A review of Parkinson's disease". Br. Med. Bull. 86 (1): 109–27.  
  9. ^ Barnett-Cowan, M; Dyde, RT; Foxe, SH; Moro, E; Hutchison, WD; Harris, LR (June 2010). "Multisensory determinants of orientation perception in Parkinson's disease". Neuroscience 167 (4): 1138–1150.  
  10. ^ Nuytemans, K; Theuns, J; Cruts, M; Van Broeckhoven, C (July 2010) [18 May 2010]. genes: a mutation update"LRRK2, and PARK7, PINK1, PARK2, SNCA"Genetic etiology of Parkinson disease associated with mutations in the .  
  11. ^ a b Galpern, WR; Lang, AE (March 2006) [17 February 2006]. "Interface between tauopathies and synucleinopathies: a tale of two proteins".  
  12. ^ a b Aarsland, D; Londos, E; Ballard, C (April 2009) [28 January 2009]. "Parkinson's disease dementia and dementia with Lewy bodies: different aspects of one entity".  
  13. ^ a b Cooper, G; Eichhorn, G; Rodnitzky, RL (2008). "Parkinson's disease". In Conn, PM. Neuroscience in medicine. Totowa, NJ: Humana Press. pp. 508–512.  
  14. ^ Rodriguez-Oroz, MC; Jahanshahi, M; Krack, P; Litvan, I; Macias, R; Bezard, E; Obeso, JA (December 2009). "Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms".  
  15. ^ Banich, MT; Compton, RJ (2011). "Motor control". Cognitive neuroscience. Belmont, CA: Wadsworth, Cengage learning. pp. 108–144.  
  16. ^ Longmore, M; Wilkinson, IB; Turmezei, T; Cheung, CK (4 January 2007). Oxford Handbook of Clinical Medicine.  
  17. ^ Fung, VS; Thompson, PD (2007). "Rigidity and spasticity". In Tolosa, E; Jankovic. Parkinson's disease and movement disorders. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 504–13.  
  18. ^ O'Sullivan, SB; Schmitz, TJ (2007). "Parkinson's Disease". Physical Rehabilitation (5th ed.). Philadelphia: F.A. Davis. pp. 856–7. 
  19. ^ a b Yao, S.C.; Hart, A.D.; Terzella, M.J. (May 2013). "An evidence-based osteopathic approach to Parkinson disease". Osteopathic Family Physician 5 (3): 96–101.  
  20. ^ Russell, JA; Ciucci, MR; Connor, NP; Schallert, T (23 June 2010). "Targeted exercise therapy for voice and swallow in persons with Parkinson's disease".  
  21. ^ a b c d e Caballol, N; Martí, MJ; Tolosa, E (September 2007). "Cognitive dysfunction and dementia in Parkinson disease".  
  22. ^ Murray, ED; Buttner, EA; Price, BH (2012). "Depression and Psychosis in Neurological Practice". In Bradley, WG; Daroff, RB; Fenichel, GM; Jankovic, J. Bradley's Neurology in Clinical Practice: Expert Consult – Online and Print, 6e (Bradley, Neurology in Clinical Practice e-dition 2v Set) 1 (6th ed.). Philadelphia, PA: Elsevier/Saunders. pp. 102–103.  
  23. ^ a b c Ceravolo R, Frosini D, Rossi C, Bonuccelli U; Frosini; Rossi; Bonuccelli (December 2009). "Impulse control disorders in Parkinson's disease: definition, epidemiology, risk factors, neurobiology and management". Parkinsonism Relat. Disord. 15 (Suppl 4): S111–5.  
  24. ^ Shergill SS, Walker Z, Le Katona C; Walker; Le Katona (October 1998). "A preliminary investigation of laterality in Parkinson's disease and susceptibility to psychosis". J. Neurol. Neurosurg. Psychiatr. 65 (4): 610–1.  
  25. ^ Friedman JH (June 2010). "Parkinson's disease psychosis 2010: A review article". Parkinsonism Relat. Disord. 16 (9): 553–60.  
  26. ^ a b c d e f g h i j Barichella M, Cereda E, Pezzoli G; Cereda; Pezzoli (October 2009). "Major nutritional issues in the management of Parkinson's disease". Mov. Disord. 24 (13): 1881–92.  
  27. ^ Armstrong RA (March 2008). "Visual signs and symptoms of Parkinson's disease". Clin. Exp. Optom. 91 (2): 129–38.  
  28. ^ Noyce AJ, Bestwick JP, Silveira-Moriyama L et al. (December 2012). "Meta-analysis of early nonmotor features and risk factors for Parkinson disease". Annals of Neurology 72 (6): 893–901.  
  29. ^ Van Maele-Fabry G, Hoet P, Vilain F, Lison D; Hoet; Vilain; Lison (October 2012). "Occupational exposure to pesticides and Parkinson's disease: a systematic review and meta-analysis of cohort studies". Environ Int 46: 30–43.  
  30. ^ a b c d e f g h i j k l m n o de Lau LM, Breteler MM; Breteler (June 2006). "Epidemiology of Parkinson's disease". Lancet Neurol. 5 (6): 525–35.  
  31. ^ a b IOM (Institute of Medicine), ed. (2009). "Neurologic disorders". Veterans and Agent Orange: Update 2008. Washington D.C.: The National Academies press. pp. 510–45.  
  32. ^ Freire C, Koifman S; Koifman (October 2012). "Pesticide exposure and Parkinson's disease: epidemiological evidence of association". Neurotoxicology 33 (5): 947–71.  
  33. ^ Tanner CM, Kamel F, Ross GW et al. (January 2011). "Rotenone, Paraquat and Parkinson's Disease".  
  34. ^ a b c d e f g h i j Lesage S, Brice A; Brice (April 2009). "Parkinson's disease: from monogenic forms to genetic susceptibility factors". Hum. Mol. Genet. 18 (R1): R48–59.  
  35. ^ IPDGC; Nalls, MA; Plagnol, V; Hernandez, DG; Sharma, M; Sheerin, UM; Saad, M; Simón-Sánchez, J; Schulte, C (2011). "Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies". Lancet 377 (9766): 641–49.  
  36. ^ a b c d e f g h Obeso JA, Rodríguez-Oroz MC, Benitez-Temino B et al. (2008). "Functional organization of the basal ganglia: therapeutic implications for Parkinson's disease". Mov. Disord. 23 (Suppl 3): S548–59.  
  37. ^ a b c Dickson DV (2007). "Neuropathology of movement disorders". In Tolosa E, Jankovic JJ. Parkinson's disease and movement disorders. Hagerstown, MD: Lippincott Williams & Wilkins. pp. 271–83.  
  38. ^ Jubault T, Brambati SM, Degroot C et al. (2009). Gendelman, Howard E., ed. "Regional brain stem atrophy in idiopathic Parkinson's disease detected by anatomical MRI". PLoS ONE 4 (12): e8247.  
  39. ^ a b c d e f g h i j k l m n o p q r s Obeso JA, Rodriguez-Oroz MC, Goetz CG et al. (May 2010). "Missing pieces in the Parkinson's disease puzzle". Nat. Med. 16 (6): 653–61.  
  40. ^ a b c Schulz-Schaeffer WJ (August 2010). "The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia". Acta Neuropathol. 120 (2): 131–43.  
  41. ^ Hirsch EC (December 2009). "Iron transport in Parkinson's disease". Parkinsonism Relat. Disord. 15 (Suppl 3): S209–11.  
  42. ^ a b The National Collaborating Centre for Chronic Conditions, ed. (2006). "Diagnosing Parkinson's Disease". Parkinson's Disease. London: Royal College of Physicians. pp. 29–47.  
  43. ^ Poewe W, Wenning G; Wenning (November 2002). "The differential diagnosis of Parkinson's disease". Eur. J. Neurol. 9 (Suppl 3): 23–30.  
  44. ^ a b c d e Brooks DJ (April 2010). "Imaging approaches to Parkinson disease". J. Nucl. Med. 51 (4): 596–609.  
  45. ^ Costa J, Lunet N, Santos C, Santos J, Vaz-Carneiro A; Lunet; Santos; Santos; Vaz-Carneiro (2010). "Caffeine exposure and the risk of Parkinson's disease: a systematic review and meta-analysis of observational studies". J. Alzheimers Dis. 20 (Suppl 1): S221–38.  
  46. ^ Quik M, Huang LZ, Parameswaran N, Bordia T, Campos C, Perez XA; Huang; Parameswaran; Bordia; Campos; Perez (1 October 2009). "Multiple roles for nicotine in Parkinson's disease". Biochem Pharmacol 78 (7): 677–85.  
  47. ^ Castagnoli K, Murugesan T; Murugesan (January 2004). "Tobacco leaf, smoke and smoking, MAO inhibitors, Parkinson's disease and neuroprotection; are there links?". Neurotoxicology 25 (1–2): 279–91.  
  48. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah The National Collaborating Centre for Chronic Conditions, ed. (2006). "Symptomatic pharmacological therapy in Parkinson’s disease". Parkinson's Disease. London: Royal College of Physicians. pp. 59–100.  
  49. ^ a b Bronstein JM, Tagliati M, Alterman RL et al. (February 2011). "Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues". Arch. Neurol. 68 (2): 165.  
  50. ^ The National Collaborating Centre for Chronic Conditions, ed. (2006). "Palliative care in Parkinson’s disease". Parkinson's Disease. London: Royal College of Physicians. pp. 147–51.  
  51. ^ a b Tolosa E, Katzenschlager R (2007). "Pharmacological management of Parkinson's disease". In Tolosa E, Jankovic JJ. Parkinson's disease and movement disorders. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 110–45.  
  52. ^ Goldenberg MM (October 2008). "Medical management of Parkinson's disease". P & T 33 (10): 590–606.  
  53. ^ a b The National Collaborating Centre for Chronic Conditions, ed. (2006). "Non-motor features of Parkinson's disease". Parkinson's Disease. London: Royal College of Physicians. pp. 113–33.  
  54. ^ Hasnain M, Vieweg WV, Baron MS, Beatty-Brooks M, Fernandez A, Pandurangi AK; Vieweg; Baron; Beatty-Brooks; Fernandez; Pandurangi (July 2009). "Pharmacological management of psychosis in elderly patients with parkinsonism". Am. J. Med. 122 (7): 614–22.  
  55. ^ Gagne JJ, Power MC; Power (Mar 2010). "Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis". Neurology 74 (12): 995–1002.  
  56. ^ a b c d The National Collaborating Centre for Chronic Conditions, ed. (2006). "Surgery for Parkinson’s disease". Parkinson's Disease. London: Royal College of Physicians. pp. 101–11.  
  57. ^ a b c d e The National Collaborating Centre for Chronic Conditions, ed. (2006). "Other key interventions". Parkinson's Disease. London: Royal College of Physicians. pp. 135–46.  
  58. ^ a b Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL; Richards; Taylor; Taylor; Campbell (April 2008). "The effectiveness of exercise interventions for people with Parkinson's disease: a systematic review and meta-analysis". Mov. Disord. 23 (5): 631–40.  
  59. ^ Dereli EE, Yaliman A; Yaliman (April 2010). "Comparison of the effects of a physiotherapist-supervised exercise programme and a self-supervised exercise programme on quality of life in patients with Parkinson's disease". Clin Rehabil 24 (4): 352–62.  
  60. ^ O'Sullivan & Schmitz 2007, pp. 873, 876
  61. ^ O'Sullivan & Schmitz 2007, p. 879
  62. ^ O'Sullivan & Schmitz 2007, p. 877
  63. ^ O'Sullivan & Schmitz 2007, p. 880
  64. ^ Fox CM, Ramig LO, Ciucci MR, Sapir S, McFarland DH, Farley BG; Ramig; Ciucci; Sapir; McFarland; Farley (November 2006). "The science and practice of LSVT/LOUD: neural plasticity-principled approach to treating individuals with Parkinson disease and other neurological disorders". Semin. Speech. Lang. 27 (4): 283–99.  
  65. ^ Dixon L, Duncan D, Johnson P et al. (2007). Deane, Katherine, ed. "Occupational therapy for patients with Parkinson's disease". Cochrane Database of Systematic Reviews (3): CD002813.  
  66. ^ Ferrell B, Connor SR, Cordes A, Dahlin CM, Fine PG, Hutton N et al. (2007). "The national agenda for quality palliative care: the National Consensus Project and the National Quality Forum". J Pain Symptom Manage 33 (6): 737–44.  
  67. ^ a b Lorenzl S, Nübling G, Perrar KM, Voltz R; Nübling; Perrar; Voltz (2013). "Palliative treatment of chronic neurologic disorders". Handb Clin Neurol. Handbook of Clinical Neurology 118: 133–9.  
  68. ^ a b Ghoche R (2012). "The conceptual framework of palliative care applied to advanced Parkinson's disease.". Parkinsonism Relat Disord 18 (Suppl 3): S2–5.  
  69. ^ a b c Wilcox SK (2010). "Extending palliative care to patients with Parkinson's disease". Br J Hosp Med (Lond) 71 (1): 26–30.  
  70. ^ Moens K, Higginson IJ, Harding R et al. (2014). "Are there differences in the prevalence of palliative care-related problems in people living with advanced cancer and eight non-cancer conditions? A systematic review". J Pain Symptom Manage. Online first (4): 660–677.  
  71. ^ Casey G (2013). "Parkinson's disease: a long and difficult journey.". Nurs N Z 19 (7): 20–4.  
  72. ^ Koch G (2010). "rTMS effects on levodopa induced dyskinesias in Parkinson's disease patients: searching for effective cortical targets". Restor. Neurol. Neurosci. 28 (4): 561–8.  
  73. ^ Platz T, Rothwell JC; Rothwell (2010). "Brain stimulation and brain repair—rTMS: from animal experiment to clinical trials—what do we know?". Restor. Neurol. Neurosci. 28 (4): 387–98.  
  74. ^ Arias P, Vivas J, Grieve KL, Cudeiro J; Vivas; Grieve; Cudeiro (September 2010). "Controlled trial on the effect of 10 days low-frequency repetitive transcranial magnetic stimulation (rTMS) on motor signs in Parkinson's disease". Mov. Disord. 25 (12): 1830–8.  
  75. ^ Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ; Gronseth; Perlmutter; Reich; Zesiewicz; Weiner; Quality Standards Subcommittee of the American Academy of Neurology (April 2006). "Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology 66 (7): 976–82.  
  76. ^ Lee MS, Lam P, Ernst E; Lam; Ernst (December 2008). "Effectiveness of tai chi for Parkinson's disease: a critical review". Parkinsonism Relat. Disord. 14 (8): 589–94.  
  77. ^ Lee MS, Ernst E; Ernst (January 2009). "Qigong for movement disorders: A systematic review". Mov. Disord. 24 (2): 301–3.  
  78. ^ Lee MS, Shin BC, Kong JC, Ernst E; Shin; Kong; Ernst (August 2008). "Effectiveness of acupuncture for Parkinson's disease: a systematic review". Mov. Disord. 23 (11): 1505–15.  
  79. ^ Katzenschlager R, Evans A, Manson A et al. (2004). "Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study". J. Neurol. Neurosurg. Psychiatr. 75 (12): 1672–7.  
  80. ^ Ladha SS, Walker R, Shill HA; Walker; Shill (May 2005). "Case of neuroleptic malignant-like syndrome precipitated by abrupt fava bean discontinuance". Mov. Disord. 20 (5): 630–1.  
  81. ^ Raguthu L, Varanese S, Flancbaum L, Tayler E, Di Rocco A; Varanese; Flancbaum; Tayler; Di Rocco (October 2009). "Fava beans and Parkinson's disease: useful 'natural supplement' or useless risk?". Eur. J. Neurol. 16 (10): e171.  
  82. ^ a b c d e f g h i j k l Poewe W (December 2006). "The natural history of Parkinson's disease". J. Neurol. 253 (Suppl 7): VII2–6.  
  83. ^ a b c García Ruiz PJ (December 2004). "Prehistoria de la enfermedad de Parkinson" . Neurologia (in Spanish; Castilian) 19 (10): 735–7.  
  84. ^ a b Lanska DJ (2010). "Chapter 33: the history of movement disorders". Handb. Clin. Neurol. Handbook of Clinical Neurology 95: 501–46.  
  85. ^ Koehler PJ, Keyser A; Keyser (September 1997). "Tremor in Latin texts of Dutch physicians: 16th–18th centuries". Mov. Disord. 12 (5): 798–806.  
  86. ^ a b c d e f g h Lees AJ (September 2007). "Unresolved issues relating to the shaking palsy on the celebration of James Parkinson's 250th birthday". Mov. Disord. 22 (Suppl 17): S327–34.  
  87. ^ Louis ED (November 1997). "The shaking palsy, the first forty-five years: a journey through the British literature". Mov. Disord. 12 (6): 1068–72.  
  88. ^ a b c Fahn S (2008). "The history of dopamine and levodopa in the treatment of Parkinson's disease". Mov. Disord. 23 (Suppl 3): S497–508.  
  89. ^ Guridi J, Lozano AM; Lozano (November 1997). "A brief history of pallidotomy". Neurosurgery 41 (5): 1169–80; discussion 1180–3.  
  90. ^ Hornykiewicz O (2002). "L-DOPA: from a biologically inactive amino acid to a successful therapeutic agent". Amino Acids 23 (1–3): 65–70.  
  91. ^ Coffey RJ (March 2009). "Deep brain stimulation devices: a brief technical history and review". Artif. Organs 33 (3): 208–20.  
  92. ^ a b c d e Findley LJ (September 2007). "The economic impact of Parkinson's disease". Parkinsonism Relat. Disord. 13 (Suppl): S8–S12.  
  93. ^ a b "'"Parkinson's – 'the shaking palsy. GlaxoSmithKline. 1 April 2009. 
  94. ^ "National Parkinson Foundation – Mission". Retrieved 28 March 2011. 
  95. ^ "Education: Joy in Giving". Time. 18 January 1960. Retrieved 2 April 2011. 
  96. ^ "About PDF". Parkinson's Disease Foundation. Retrieved 14 October 2014. 
  97. ^ "American Parkinson Disease Association: Home". American Parkinson Disease Association. Retrieved 9 August 2010. 
  98. ^ "About EPDA". European Parkinson's Disease Association. 2010. Retrieved 9 August 2010. 
  99. ^ a b Davis P (3 May 2007). "Michael J. Fox". The TIME 100 ( 
  100. ^ a b c Brockes E (11 April 2009). "'It's the gift that keeps on taking'". The Guardian. Retrieved 25 October 2010. 
  101. ^ "Michael J. Fox to be made honorary doctor at Karolinska Institutet". Karolinska Institutet. 5 March 2010. Retrieved 2 April 2011. 
  102. ^ Roelofs T (10 May 2010). "Tour de France bicyclist Davis Phinney talks about life with Parkinson's Disease". The Grand Rapids Press. Retrieved 25 October 2010. 
  103. ^ Macur, Juliet (26 March 2008). "For the Phinney Family, a Dream and a Challenge". The New York Times. Retrieved 25 May 2013. About 1.5 million Americans have received a diagnosis of Parkinson’s disease, but only 5 to 10 percent learn of it before age 40, according to the National Parkinson Foundation. Davis Phinney was among the few. 
  104. ^ "Who We Are". Davis Phinney Foundation. Retrieved 18 January 2012. 
  105. ^ Emanuel, W (19 October 2010). "Davis Phinney foundation launches exercise-focused tools to help people live well with Parkinson's" (Press release). Davis Phinney foundation. Retrieved 2 April 2011. 
  106. ^ Macur, Juliet (26 March 2008). "For the Phinney Family, a Dream and a Challenge". The New York Times. Retrieved 25 May 2013. ...[Davis Phinney] started an organization in his name, the Davis Phinney Foundation, and gives motivational speeches to Parkinson’s patients, pushing them to celebrate every victory, however small, like tying their shoes. The high doses of medication he needs to get through those talks cause side effects, like the involuntary swaying of his head. But he endures. 
  107. ^ Brey RL (April 2006). "Muhammad Ali's Message: Keep Moving Forward". Neurology Now (American Academy of Neurology) 2 (2): 8. Retrieved 2 April 2011. 
  108. ^ a b Matthews W (April 2006). "Ali's Fighting Spirit". Neurology Now (American Academy of Neurology) 2 (2): 10–23. Retrieved 2 April 2011. 
  109. ^ Tauber P (17 July 1988). "Ali: Still Magic". New York Times. Retrieved 2 April 2011. 
  110. ^ a b Dimond PF (16 August 2010). "No New Parkinson Disease Drug Expected Anytime Soon". GEN news highlights. GEN-Genetic Engineering & Biotechnology News. 
  111. ^ Langston JW, Ballard P, Tetrud JW, Irwin I; Ballard; Tetrud; Irwin (February 1983). "Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis". Science 219 (4587): 979–80.  
  112. ^ Cicchetti F, Drouin-Ouellet J, Gross RE; Drouin-Ouellet; Gross (September 2009). "Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models?". Trends Pharmacol. Sci. 30 (9): 475–83.  
  113. ^ Harvey BK, Wang Y, Hoffer BJ; Wang; Hoffer (2008). "Transgenic rodent models of Parkinson's disease". Acta Neurochir. Suppl. Acta Neurochirurgica Supplementum 101: 89–92.  
  114. ^ Blum, et al.,; Torch, S; Lambeng, N; Nissou, M; Benabid, AL; Sadoul, R; Verna, JM (October 2001). "Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease". Progress in Neurobiology 65 (2): 135–172.  
  115. ^ Feng, LR, Maguire-Zeiss KA; Maguire-Zeiss (2010). "Gene Therapy in Parkinson's Disease: Rationale and Current Status". CNS Drugs 24 (3): 177–92.  
  116. ^ Lewitt PA, Rezai AR, Leehey MA et al. (April 2011). "AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial". Lancet Neurol 10 (4): 309–19.  
  117. ^ "Neurologix Files to Liquidate Under Chapter 7 Bankruptcy". 
  118. ^ "World's first Parkinson's vaccine is trialled". New Scientist. 7 June 2012. 
  119. ^ Redmond DE (October 2002). "Cellular replacement therapy for Parkinson's disease—where we are today?". The Neuroscientist 8 (5): 457–88.  
  120. ^ "Stem Cell Research Aims to Tackle Parkinson's Disease". Retrieved 16 April 2010. 


Since early in the 1980s, fetal, porcine, carotid or retinal tissues have been used in cell transplants, in which dissociated cells are injected into the substantia nigra in the hope that they will incorporate themselves into the brain in a way that replaces the dopamine-producing cells that have been lost.[39] Although there was initial evidence of mesencephalic dopamine-producing cell transplants being beneficial, double-blind trials to date indicate that cell transplants produce no long-term benefit.[39] An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonias.[119] Stem cell transplants are a recent research target, because stem cells are easy to manipulate and stem cells transplanted into the brains of rodents and monkeys have been found to survive and reduce behavioral abnormalities.[39][120] Nevertheless, use of fetal stem cells is controversial.[39] It has been proposed that effective treatments may be developed in a less controversial way by use of induced pluripotent stem cells taken from adults.[39]

Neural transplantation

Investigations on neuroprotection are at the forefront of PD research. Several molecules have been proposed as potential treatments.[39] However, none of them have been conclusively demonstrated to reduce degeneration.[39] Agents currently under investigation include anti-apoptotics (omigapil, CEP-1347), antiglutamatergics, monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrials (coenzyme Q10, creatine), calcium channel blockers (isradipine) and growth factors (GDNF).[39] Preclinical research also targets alpha-synuclein.[110] A vaccine that primes the human immune system to destroy alpha-synuclein, PD01A (developed by Austrian company, Affiris), has entered clinical trials in humans.[118]

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

Neuroprotective treatments

Gene therapy involves the use of a non-infectious virus to shuttle a gene into a part of the brain. The gene used leads to the production of an enzyme that helps to manage PD symptoms or protects the brain from further damage.[39][115] In 2010 there were four clinical trials using gene therapy in PD.[39] There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown.[39] One of these reported positive results in 2011,[116] but the company filed for bankruptcy in March 2012.[117]

Gene therapy

PD is not known to occur naturally in any species other than humans, although animal models which show some features of the disease are used in research. The appearance of parkinsonian symptoms in a group of drug addicts in the early 1980s who consumed a contaminated batch of the synthetic opiate MPPP led to the discovery of the chemical MPTP as an agent that causes a parkinsonian syndrome in non-human primates as well as in humans.[111] Other predominant toxin-based models employ the insecticide rotenone, the herbicide paraquat and the fungicide maneb.[112] Models based on toxins are most commonly used in primates. Transgenic rodent models that replicate various aspects of PD have been developed.[113] Using the neurotoxin 6-hydroxydopamine, also known as 6-OHDA, it creates a model of Parkinson’s disease in rats by targeting and destroying dopaminergic neurons in the nigrostriatal pathway when injected into the substantia nigra [114]

Animal models

There is little prospect of dramatic new PD treatments expected in a short time frame.[110] Currently active research directions include the search for new animal models of the disease and studies of the potential usefulness of gene therapy, stem cell transplants and neuroprotective agents.[39]


Muhammad Ali has been called the "world's most famous Parkinson's patient".[107] He was 42 at diagnosis although he showed signs of Parkinson's when he was 38.[108] Whether he has PD or a parkinsonism related to boxing is unresolved.[108][109]

Professional cyclist and Olympic medalist Davis Phinney, who was diagnosed with young onset Parkinson's at age 40, started a foundation in his name in 2004 to support Parkinson's research, focusing on quality of life for people with the disease.[102][103] The Davis Phinney Foundation's mission is to help people living with Parkinson's disease live well by providing them with information, inspiration and tools.[104][105] Phinney gives motivational speeches to people with Parkinson’s, pushing them to celebrate every victory, however small, like tying their shoes.[106]

Actor Michael J. Fox has PD and has greatly increased the public awareness of the disease. Fox was diagnosed in 1991 when he was 30, but kept his condition secret from the public for seven years.[99] He has written two autobiographies in which his fight against the disease plays a major role,[100] and appeared before the United States Congress without medication to illustrate the effects of the disease.[100] The Michael J. Fox Foundation aims to develop a cure for Parkinson's disease. In recent years it has been the major Parkinson's fundraiser in the U.S., providing $140 million in funding between 2001 and 2008.[100] Fox was named one of the 100 people "whose power, talent or moral example is transforming the world" in 2007 by Time magazine,[99] and he received an honorary doctorate in medicine from Karolinska Institutet for his contributions to research in Parkinson's disease.[101]

Notable cases

11 April, the birthday of James Parkinson, has been designated as Parkinson's disease day.[86][93] A red tulip was chosen by international organizations as the symbol of the disease in 2005: it represents the James Parkinson Tulip National Parkinson Foundation, which has provided more than $180 million in care, research and support services since 1982,[94] Parkinson's Disease Foundation, which has distributed more than $105 million for research and $44 million for education and advocacy programs since its founding in 1957 by William Black;[95][96] the American Parkinson Disease Association, founded in 1961;[97] and the European Parkinson's Disease Association, founded in 1992.[98]


The costs of PD to society are high, but precise calculations are difficult due to methodological issues in research and differences between countries.[92] The annual cost in the UK is estimated to be between 449 million and 3.3 billion pounds, while the cost per patient per year in the U.S. is probably around $10,000 and the total burden around 23 billion dollars.[92] The largest share of direct cost comes from inpatient care and nursing homes, while the share coming from medication is substantially lower.[92] Indirect costs are high, due to reduced productivity and the burden on caregivers.[92] In addition to economic costs, PD reduces quality of life of those with the disease and their caregivers.[92]

Muhammad Ali at the World Economic Forum in Davos, at the age of 64. He has shown signs of parkinsonism since the age of 38.


Society and culture

Anticholinergics and surgery (lesioning of the corticospinal pathway or some of the basal ganglia structures) were the only treatments until the arrival of levodopa, which reduced their use dramatically.[84][89] Levodopa was first synthesized in 1911 by Casimir Funk, but it received little attention until the mid 20th century.[88] It entered clinical practice in 1967 and brought about a revolution in the management of PD.[88][90] By the late 1980s deep brain stimulation emerged as a possible treatment.[91]

In 1912 Frederic Lewy described microscopic particles in affected brains, later named "Lewy bodies".[86] In 1919 Konstantin Tretiakoff reported that the substantia nigra was the main cerebral structure affected, but this finding was not widely accepted until it was confirmed by further studies published by Rolf Hassler in 1938.[86] The underlying biochemical changes in the brain were identified in the 1950s, due largely to the work of Arvid Carlsson on the neurotransmitter dopamine and Oleh Hornykiewicz on its role on PD.[88] In 1997, alpha-synuclein was found to be the main component of Lewy bodies.[40]

In 1817 an English doctor, James Parkinson, published his essay reporting six cases of paralysis agitans.[86] An Essay on the Shaking Palsy described the characteristic resting tremor, abnormal posture and gait, paralysis and diminished muscle strength, and the way that the disease progresses over time.[86][87] Early neurologists who made further additions to the knowledge of the disease include Trousseau, Gowers, Kinnier Wilson and Erb, and most notably Jean-Martin Charcot, whose studies between 1868 and 1881 were a landmark in the understanding of the disease.[86] Among other advances, he made the distinction between rigidity, weakness and bradykinesia.[86] He also championed the renaming of the disease in honor of James Parkinson.[86]

Several early sources, including an Egyptian papyrus, an Ayurvedic medical treatise, the Bible, and Galen's writings, describe symptoms resembling those of PD.[83] After Galen there are no references unambiguously related to PD until the 17th century.[83] In the 17th and 18th centuries, several authors wrote about elements of the disease, including Sylvius, Gaubius, Hunter and Chomel.[83][84][85]

An 1893 photograph of Jean-Martin Charcot, who made important contributions to the understanding of the disease and proposed its current name honoring James Parkinson


Many risk factors and protective factors have been proposed, sometimes in relation to theories concerning possible mechanisms of the disease, however none have been conclusively related to PD by empirical evidence. When epidemiological studies have been carried out in order to test the relationship between a given factor and PD, they have often been flawed and their results have in some cases been contradictory.[30] The most frequently replicated relationships are an increased risk of PD in those exposed to pesticides, and a reduced risk in smokers.[30]

PD is the second most common neurodegenerative disorder after Alzheimer's disease and affects approximately seven million people globally and one million people in the United States.[19][30] The prevalence (proportion in a population at a given time) of PD is about 0.3% of the whole population in industrialized countries. PD is more common in the elderly and prevalence rises from 1% in those over 60 years of age to 4% of the population over 80.[30] The mean age of onset is around 60 years, although 5–10% of cases, classified as young onset, begin between the ages of 20 and 50.[6] PD may be less prevalent in those of African and Asian ancestry, although this finding is disputed.[30] Some studies have proposed that it is more common in men than women, but others failed to detect any differences between the two sexes.[30] The incidence of PD is between 8 and 18 per 100,000 person–years.[30]


The life expectancy of people with PD is reduced.[82] Mortality ratios are around twice those of unaffected people.[82] Cognitive decline and dementia, old age at onset, a more advanced disease state and presence of swallowing problems are all mortality risk factors. On the other hand a disease pattern mainly characterized by tremor as opposed to rigidity predicts an improved survival.[82] Death from aspiration pneumonia is twice as common in individuals with PD as in the healthy population.[82]

Since current therapies improve motor symptoms, disability at present is mainly related to non-motor features of the disease.[39] Nevertheless, the relationship between disease progression and disability is not linear. Disability is initially related to motor symptoms.[82] As the disease advances, disability is more related to motor symptoms that do not respond adequately to medication, such as swallowing/speech difficulties, and gait/balance problems; and also to motor complications, which appear in up to 50% of individuals after 5 years of levodopa usage.[82] Finally, after ten years most people with the disease have autonomic disturbances, sleep problems, mood alterations and cognitive decline.[82] All of these symptoms, especially cognitive decline, greatly increase disability.[39][82]

Motor symptoms, if not treated, advance aggressively in the early stages of the disease and more slowly later. Untreated, individuals are expected to lose independent ambulation after an average of eight years and be bedridden after ten years.[82] However, it is uncommon to find untreated people nowadays. Medication has improved the prognosis of motor symptoms, while at the same time it is a new source of disability because of the undesired effects of levodopa after years of use.[82] In people taking levodopa, the progression time of symptoms to a stage of high dependency from caregivers may be over 15 years.[82] However, it is hard to predict what course the disease will take for a given individual.[82] Age is the best predictor of disease progression.[39] The rate of motor decline is greater in those with less impairment at the time of diagnosis, while cognitive impairment is more frequent in those who are over 70 years of age at symptom onset.[39]

PD invariably progresses with time. A severity rating method known as the Unified Parkinson's Disease Rating Scale (UPDRS) is the most commonly used metric for clinical study. A modified version known as the MDS-UPDRS is also sometimes used. An older scaling method known as the Hoehn and Yahr scale (originally published in 1967), and a similar scale known as the Modified Hoehn and Yahr scale, have also been commonly used. The Hoehn and Yahr scale defines five basic stages of progression.

Global burden of Parkinson's disease, measured in disability-adjusted life years per 100,000 inhabitants in 2004
  no data
  < 5
  > 80


Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias.[72] Its usefulness in PD is an open research topic,[73] although recent studies have shown no effect by rTMS.[74] Several nutrients have been proposed as possible treatments; however there is no evidence that vitamins or food additives improve symptoms.[75] There is no evidence to substantiate that acupuncture and practice of Qigong, or T'ai chi, have any effect on the course of the disease or symptoms. Further research on the viability of Tai chi for balance or motor skills are necessary.[76][77][78] Fava beans and velvet beans are natural sources of levodopa and are eaten by many people with PD. While they have shown some effectiveness in clinical trials,[79] their intake is not free of risks. Life-threatening adverse reactions have been described, such as the neuroleptic malignant syndrome.[80][81]

Levodopa and proteins use the same transportation system in the intestine and the blood–brain barrier, thereby competing for access.[26] When they are taken together, this results in a reduced effectiveness of the drug.[26] Therefore, when levodopa is introduced, excessive protein consumption is discouraged and well balanced Mediterranean diet is recommended. In advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons.[26] To minimize interaction with proteins, levodopa should be taken 30 minutes before meals.[26] At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.[26]

Muscles and nerves that control the digestive process may be affected by PD, resulting in constipation and gastroparesis (food remaining in the stomach for a longer period of time than normal).[26] A balanced diet, based on periodical nutritional assessments, is recommended and should be designed to avoid weight loss or gain and minimize consequences of gastrointestinal dysfunction.[26] As the disease advances, swallowing difficulties (dysphagia) may appear. In such cases it may be helpful to use thickening agents for liquid intake and an upright posture when eating, both measures reducing the risk of choking. Gastrostomy to deliver food directly into the stomach is possible in severe cases.[26]

Other treatments

Along with offering emotional support to both the patient and family, palliative care serves an important role in addressing goals of care. People with Parkinson’s may have many difficult decisions to make as the disease progresses such as wishes for feeding tube, non-invasive ventilator, and tracheostomy; wishes for or against cardiopulmonary resuscitation; and when to use hospice care.[67] Palliative care team members can help answer questions and guide people with Parkinson’s on these complex and emotional topics to help them make the best decision based on their own values.[71][69]

Palliative care should be involved earlier, rather than later in the disease course.[68][69] Palliative care specialists can help with physical symptoms, emotional factors such as loss of function and jobs, depression, fear, and existential concerns.[70][68][69]

Palliative care is specialized medical care for people with serious illnesses, including Parkinson’s. The goal of this speciality is to improve quality of life for both the person suffering from Parkinson’s and the family by providing relief from the symptoms, pain, and stress of illnesses.[66] As Parkinson’s is not a curable disease, all treatments are focused on slowing decline and improving quality of life, and are therefore palliative in nature.[67]

Palliative care

One of the most widely practiced treatments for speech disorders associated with Parkinson's disease is the Lee Silverman voice treatment (LSVT).[57][64] Speech therapy and specifically LSVT may improve speech.[57] Occupational therapy (OT) aims to promote health and quality of life by helping people with the disease to participate in as many of their daily living activities as possible.[57] There have been few studies on the effectiveness of OT and their quality is poor, although there is some indication that it may improve motor skills and quality of life for the duration of the therapy.[57][65]

There is some evidence that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality.[57][58] Regular physical exercise with or without physiotherapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.[58] However, when an exercise program is performed under the supervision of a physiotherapist, there are more improvements in motor symptoms, mental and emotional functions, daily living activities, and quality of life compared to a self-supervised exercise program at home.[59] In terms of improving flexibility and range of motion for people experiencing rigidity, generalized relaxation techniques such as gentle rocking have been found to decrease excessive muscle tension. Other effective techniques to promote relaxation include slow rotational movements of the extremities and trunk, rhythmic initiation, diaphragmatic breathing, and meditation techniques.[60] As for gait and addressing the challenges associated with the disease such as hypokinesia (slowness of movement), shuffling and decreased arm swing; physiotherapists have a variety of strategies to improve functional mobility and safety. Areas of interest with respect to gait during rehabilitation programs focus on but are not limited to improving gait speed, base of support, stride length, trunk and arm swing movement. Strategies include utilizing assistive equipment (pole walking and treadmill walking), verbal cueing (manual, visual and auditory), exercises (marching and PNF patterns) and altering environments (surfaces, inputs, open vs. closed).[61] Strengthening exercises have shown improvements in strength and motor function for people with primary muscular weakness and weakness related to inactivity with mild to moderate Parkinson’s disease. However, reports show a significant interaction between strength and the time the medications was taken. Therefore, it is recommended that people with PD should perform exercises 45 minutes to one hour after medications, when they are at their best.[62] Also, due to the forward flexed posture, and respiratory dysfunctions in advanced Parkinson’s disease, deep diaphragmatic breathing exercises are beneficial in improving chest wall mobility and vital capacity.[63] Exercise may improve constipation.[26]


Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa, the number of operations declined.[56] Studies in the past few decades have led to great improvements in surgical techniques, so that surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient.[56] Surgery for PD can be divided in two main groups: lesional and deep brain stimulation (DBS). Target areas for DBS or lesions include the thalamus, the globus pallidus or the subthalamic nucleus.[56] Deep brain stimulation (DBS) is the most commonly used surgical treatment, developed in the 1980s by Alim-Louis Benabid and others. It involves the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain. DBS is recommended for people who have PD with motor fluctuations and tremor inadequately controlled by medication, or to those who are intolerant to medication, as long as they do not have severe neuropsychiatric problems.[49] 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.[56]

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


Other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms. However, the evidence supporting them lacks quality, so they are not first choice treatments.[48] In addition to motor symptoms, PD is accompanied by a diverse range of symptoms. A number of drugs have been used to treat some of these problems.[53] Examples are the use of quetiapine for psychosis, cholinesterase inhibitors for dementia, and modafinil for daytime sleepiness.[53][54] A 2010 meta-analysis found that non-steroidal anti-inflammatory drugs (apart from paracetamol and aspirin), have been associated with at least a 15 percent (higher in long-term and regular users) reduction of incidence of the development of Parkinson's disease.[55]

Other drugs

MAO-B inhibitors (selegiline and rasagiline) increase the level of dopamine in the basal ganglia by blocking its metabolism. They inhibit monoamine oxidase B (MAO-B) which breaks down dopamine secreted by the dopaminergic neurons. The reduction in MAO-B activity results in increased L-DOPA in the striatum.[48] Like dopamine agonists, MAO-B inhibitors used as monotherapy improve motor symptoms and delay the need for levodopa in early disease, but produce more adverse effects and are less effective than levodopa. There are few studies of their effectiveness in the advanced stage, although results suggest that they are useful to reduce fluctuations between on and off periods.[48] An initial study indicated that selegiline in combination with levodopa increased the risk of death, but this was later disproven.[48]

MAO-B inhibitors

Apomorphine, a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD.[48] It is administered by intermittent injections or continuous subcutaneous infusions.[48] Since secondary effects such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be closely monitored.[48] Two dopamine agonists that are administered through skin patches (lisuride and rotigotine) and are useful for people in the initial stages and possibly to control off states in those in the advanced state.[51]

Dopamine agonists produce significant, although usually mild, side effects including drowsiness, hallucinations, insomnia, nausea and constipation.[48] Sometimes side effects appear even at a minimal clinically effective dose, leading the physician to search for a different drug.[48] Compared with levodopa, dopamine agonists may delay motor complications of medication use but are less effective at controlling symptoms.[48] Nevertheless, they are usually effective enough to manage symptoms in the initial years.[6] They tend to be more expensive than levodopa.[6] Dyskinesias due to dopamine agonists are rare in younger people who have PD, but along with other side effects, become more common with age at onset.[6] Thus dopamine agonists are the preferred initial treatment for earlier onset, as opposed to levodopa in later onset.[6] Agonists have been related to impulse control disorders (such as compulsive sexual activity and eating, and pathological gambling and shopping) even more strongly than levodopa.[23]

Several dopamine agonists that bind to dopaminergic post-synaptic receptors in the brain have similar effects to levodopa.[48] These were initially used for individuals experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa; they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications.[48][52] When used in late PD they are useful at reducing the off periods.[48] Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride.

Dopamine agonists

Levodopa preparations lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesias and fluctuations in the response to medication.[48] When this occurs a person with PD can change from phases with good response to medication and few symptoms ("on" state), to phases with no response to medication and significant motor symptoms ("off" state).[48] For this reason, levodopa doses are kept as low as possible while maintaining functionality.[48] Delaying the initiation of therapy with levodopa by using alternatives (dopamine agonists and MAO-B inhibitors) is common practice.[48] A former strategy to reduce motor complications was to withdraw L-DOPA medication for some time. This is discouraged now, since it can bring dangerous side effects such as neuroleptic malignant syndrome.[48] Most people with PD will eventually need levodopa and later develop motor side effects.[48]

Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of levodopa.[48] It has been used to complement levodopa; however, its usefulness is limited by possible side effects such as liver damage.[48] A similarly effective drug, entacapone, has not been shown to cause significant alterations of liver function.[48] Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.[48]

Only 5–10% of L-DOPA crosses the blood–brain barrier. The remainder is often metabolized to dopamine elsewhere, causing a variety of side effects including nausea, dyskinesias and joint stiffness.[48] Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors,[48] which help to prevent the metabolism of L-DOPA before it reaches the dopaminergic neurons, therefore reducing side effects and increasing bioavailability. They are generally given as combination preparations with levodopa.[48] Existing preparations are carbidopa/levodopa (co-careldopa) and benserazide/levodopa (co-beneldopa). Levodopa has been related to dopamine dysregulation syndrome, which is a compulsive overuse of the medication, and punding.[23] There are controlled release versions of levodopa in the form intravenous and intestinal infusions that spread out the effect of the medication. These slow-release levodopa preparations have not shown an increased control of motor symptoms or motor complications when compared to immediate release preparations.[48][51]

Levodopa has been the most widely used treatment for over 30 years.[48] L-DOPA is converted into dopamine in the dopaminergic neurons by dopa decarboxylase.[48] Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor symptoms.[48]


There is no cure for Parkinson's disease, but medications, surgery and multidisciplinary management can provide relief from the symptoms. The main families of drugs useful for treating motor symptoms are levodopa (usually combined with a dopa decarboxylase inhibitor or COMT inhibitor), dopamine agonists and MAO-B inhibitors.[48] The stage of the disease determines which group is most useful. Two stages are usually distinguished: an initial stage in which the individual with PD has already developed some disability for which he needs pharmacological treatment, then a second stage in which an individual develops motor complications related to levodopa usage.[48] Treatment in the initial stage aims for an optimal tradeoff between good symptom control and side-effects resulting from improvement of dopaminergic function. The start of levodopa (or L-DOPA) treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of delaying the onset of dyskinesias.[48] In the second stage the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication or overuse have to be managed.[48] When medications are not enough to control symptoms, surgery and deep brain stimulation can be of use.[49] In the final stages of the disease, palliative care is provided to improve quality of life.[50]

Pharmacological treatment of Parkinson's disease


Antioxidants, such as vitamins C and D, have been proposed to protect against the disease but results of studies have been contradictory and no positive effect has been proven.[30] The results regarding fat and fatty acids have been contradictory, with various studies reporting protective effects, risk-increasing effects or no effects.[30] Also, there have been preliminary indications of a possible protective role of estrogens and anti-inflammatory drugs.[30]

Caffeine consumption appears protective against Parkinson's disease with a greater decrease in risk occurring with a larger intake of caffeinated beverages such as coffee.[45] Although tobacco smoke decreases life expectancy and quality of life, it may reduce the risk of PD by a third when compared to non-smokers.[30] The basis for this effect is not known, but possibilities include an effect of nicotine as a dopamine stimulant.[30][46] Tobacco smoke contains compounds that act as MAO inhibitors that also might contribute to this effect.[47]


Computed tomography (CT) and magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal.[44] These techniques are nevertheless useful to rule out other diseases that can be secondary causes of parkinsonism, such as basal ganglia tumors, vascular pathology and hydrocephalus.[44] A specific technique of MRI, diffusion MRI, has been reported to be useful at discriminating between typical and atypical parkinsonism, although its exact diagnostic value is still under investigation.[44] Dopaminergic function in the basal ganglia can be measured with different PET and SPECT radiotracers. Examples are ioflupane (123I) (trade name DaTSCAN) and iometopane (Dopascan) for SPECT or fluorodeoxyglucose (18F) for PET.[44] A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing PD.[44]

Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process, especially in the early stages of the disease. The most widely known criteria come from the UK Parkinson's Disease Society Brain Bank and the U.S. National Institute of Neurological Disorders and Stroke.[5] The PD Society Brain Bank criteria require slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. Other possible causes for these symptoms need to be ruled out. Finally, three or more of the following features are required during onset or evolution: unilateral onset, tremor at rest, progression in time, asymmetry of motor symptoms, response to levodopa for at least five years, clinical course of at least ten years and appearance of dyskinesias induced by the intake of excessive levodopa.[5] Accuracy of diagnostic criteria evaluated at autopsy is 75–90%, with specialists such as neurologists having the highest rates.[5]

Other causes that can secondarily produce a parkinsonian syndrome are Alzheimer's disease, multiple cerebral infarction and drug-induced parkinsonism.[42] Parkinson plus syndromes such as progressive supranuclear palsy and multiple system atrophy must be ruled out.[5] Anti-Parkinson's medications are typically less effective at controlling symptoms in Parkinson plus syndromes.[5] Faster progression rates, early cognitive dysfunction or postural instability, minimal tremor or symmetry at onset may indicate a Parkinson plus disease rather than PD itself.[43] Genetic forms are usually classified as PD, although the terms familial Parkinson's disease and familial parkinsonism are used for disease entities with an autosomal dominant or recessive pattern of inheritance.[6]

A physician will diagnose Parkinson's disease from the medical history and a neurological examination.[5] There is no lab test that will clearly identify the disease, but brain scans are sometimes used to rule out disorders that could give rise to similar symptoms. People may be given levodopa and resulting relief of motor impairment tends to confirm diagnosis. The finding of Lewy bodies in the midbrain on autopsy is usually considered proof that the person had Parkinson's disease. The progress of the illness over time may reveal it is not Parkinson's disease, and some authorities recommend that the diagnosis be periodically reviewed.[5][42]

Sagittal PET scan at the level of the striatum. Hottest areas are the cortical grey matter and the striatum.
Fludeoxyglucose (18F) (FDG) PET scan of a healthy brain. Hotter areas reflect higher glucose uptake. A decreased activity in the basal ganglia can aid in diagnosing Parkinson's disease.


Other cell-death mechanisms include proteosomal and lysosomal system dysfunction and reduced mitochondrial activity.[39] Iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. It may be related to oxidative stress, protein aggregation and neuronal death, but the mechanisms are not fully understood.[41]

There is speculation of several mechanisms by which the brain cells could be lost.[39] One mechanism consists of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. This insoluble protein accumulates inside neurones forming inclusions called Lewy bodies.[8][40] According to the Braak staging, a classification of the disease based on pathological findings, Lewy bodies first appear in the olfactory bulb, medulla oblongata and pontine tegmentum, with individuals at this stage being asymptomatic. As the disease progresses, Lewy bodies later develop in the substantia nigra, areas of the midbrain and basal forebrain, and in a last step the neocortex.[8] These brain sites are the main places of neuronal degeneration in PD; however, Lewy bodies may not cause cell death and they may be protective.[39][40] In people with dementia, a generalized presence of Lewy bodies is common in cortical areas. Neurofibrillary tangles and senile plaques, characteristic of Alzheimer's disease, are not common unless the person is demented.[37]

Brain cell death

A particular conceptual model of the motor circuit and its alteration with PD has been of great influence since 1980, although some limitations have been pointed out which have led to modifications.[36] In this model, the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output.[36] Drugs that are used to treat PD, conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias.[36]

There are five major pathways in the brain connecting other brain areas with the basal ganglia. These are known as the motor, oculo-motor, associative, limbic and orbitofrontal circuits, with names indicating the main projection area of each circuit.[36] All of them are affected in PD, and their disruption explains many of the symptoms of the disease since these circuits are involved in a wide variety of functions including movement, attention and learning.[36] Scientifically, the motor circuit has been examined the most intensively.[36]

The primary symptoms of Parkinson's disease result from greatly reduced activity of dopamine-secreting cells caused by cell death in the pars compacta region of the substantia nigra.[36]

Composite of three images, one in top row (referred to in caption as A), two in second row (referred to as B). Top shows a mid-line sagittal plane of the brainstem and cerebellum. There are three circles superimposed along the brainstem and an arrow linking them from bottom to top and continuing upward and forward towards the frontal lobes of the brain. A line of text accompanies each circle: lower is
A. Schematic initial progression of Lewy body deposits in the first stages of Parkinson's disease, as proposed by Braak and colleagues
B. Localization of the area of significant brain volume reduction in initial PD compared with a group of participants without the disease in a neuroimaging study, which concluded that brain stem damage may be the first identifiable stage of PD neuropathology[38]

Composite of three images, one in top row (referred to in caption as A), two in second row (referred to as B). Top shows a mid-line sagittal plane of the brainstem and cerebellum. There are three circles superimposed along the brainstem and an arrow linking them from bottom to top and continuing upward and forward towards the frontal lobes of the brain. A line of text accompanies each circle: lower is "1. Dorsal Motor X Nucleus", middle is "2. Gain Setting Nuclei" and upper is "3. Substantia Nigra/Amygdala". A fourth line of text above the others says "4. ...". The two images at the bottom of the composite are magnetic resonance imaging (MRI) scans, one saggital and the other transverse, centred at the same brain coordinates (x=-1, y=-36, z=-49). A colored blob marking volume reduction covers most of the brainstem.


Macroscopic alterations can be noticed on cut surfaces of the brainstem, where neuronal loss can be inferred from a reduction of neuromelanin pigmentation in the substantia nigra and locus coeruleus.[37] The histopathology (microscopic anatomy) of the substantia nigra and several other brain regions shows neuronal loss and Lewy bodies in many of the remaining nerve cells. Neuronal loss is accompanied by death of astrocytes (star-shaped glial cells) and activation of the microglia (another type of glial cell). Lewy bodies are a key pathological feature of PD.[37]

The basal ganglia, a group of "brain structures" innervated by the dopaminergic system, are the most seriously affected brain areas in PD.[36] The main pathological characteristic of PD is cell death in the substantia nigra and, more specifically, the ventral (front) part of the pars compacta, affecting up to 70% of the cells by the time death occurs.[8]


Several brain cells stained in blue. The largest one, a neurone, with an approximately circular form, has a brown circular body inside it. The brown body is about 40% the diameter of the cell in which it appears.
A Lewy body (stained brown) in a brain cell of the substantia nigra in Parkinson's disease. The brown colour is positive immunohistochemistry staining for alpha-synuclein.


The LRRK2 gene (PARK8) encodes for a protein called dardarin. The name dardarin was taken from a Basque word for tremor, because this gene was first identified in families from England and the north of Spain.[8] Mutations in LRRK2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases.[8][34] There are many different mutations described in LRRK2, however unequivocal proof of causation only exists for a small number.[34]

The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of Lewy bodies.[34] Missense mutations of the gene (in which a single nucleotide is changed), and duplications and triplications of the locus containing it have been found in different groups with familial PD.[34] Missense mutations are rare.[34] On the other hand, multiplications of the SNCA locus account for around 2% of familial cases.[34] Multiplications have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age-dependent.[34]

Mutations in specific genes have been conclusively shown to cause PD. These genes code for alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2.[8][34] In most cases, people with these mutations will develop PD. With the exception of LRRK2, however, they account for only a small minority of cases of PD.[8] The most extensively studied PD-related genes are SNCA and LRRK2. Mutations in genes including SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD. Mutations in GBA are known to cause Gaucher's disease.[34] Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results.[35]

PD traditionally has been considered a non-genetic disorder; however, around 15% of individuals with PD have a first-degree relative who has the disease.[6] At least 5% of people are now known to have forms of the disease that occur because of a mutation of one of several specific genes.[34]

Rendering of parkin crystal structure, pdb code 4K95.


[30] exposure has been proposed to be a risk factor, through possible accumulation in the substantia nigra; however, studies on the issue have been inconclusive.Heavy metals [33][31][30].Agent Orange, such as herbicides, and paraquat or rotenone, such as pesticides and [32]

This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.

Copyright © World Library Foundation. All rights reserved. eBooks from World Library are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.