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| ==Overview== | | ==[[Parkinson's disease overview|Overview]]== |
| '''Parkinson's disease''' (also known as '''Parkinson disease''' or '''PD''') is a degenerative disorder of the [[central nervous system]] that often impairs the sufferer's [[motor skill]]s and speech.
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| Parkinson's disease belongs to a group of conditions called [[movement disorder]]s. It is characterized by muscle rigidity, tremor, a slowing of physical movement ([[bradykinesia]]) and, in extreme cases, a loss of physical movement ([[akinesia]]). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of [[dopamine]], which is produced in the [[dopaminergic neuron]]s of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both [[Chronic (medicine)|chronic]] and progressive. | | ==[[Parkinson's disease historical perspective|Historical Perspective]]== |
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| PD is the most common cause of [[parkinsonism]], a group of similar symptoms. PD is also called "primary parkinsonism" or "[[idiopathic]] PD" (having no known cause). While most forms of parkinsonism are idiopathic, there are some cases where the symptoms may result from toxicity, drugs, genetic mutation, head trauma, or other medical disorders.
| | ==[[Parkinson's disease pathophysiology|Pathophysiology]]== |
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| ==History== | | ==[[Parkinson's disease differential diagnosis|Differentiating Parkinson's disease from other Diseases]]== |
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| Symptoms of Parkinson's disease have been known and treated since ancient times.<ref>
| | ==[[Parkinson's disease epidemiology and demographics|Epidemiology and Demographics]]== |
| {{cite journal
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| |author=Manyam BV, Sánchez-Ramos JR
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| |title=Traditional and complementary therapies in Parkinson's disease
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| |journal=Advances in neurology
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| |volume=80
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| |pages=565-74
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| |year=1999
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| |pmid=10410773}}
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| </ref>
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| However, it was not formally recognized and its symptoms were not documented until 1817 in ''An Essay on the Shaking Palsy''<ref>
| | ==[[Parkinson's disease risk factors|Risk Factors]]== |
| {{cite journal
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| | author = Parkinson J
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| | title = An essay on the shaking palsy. 1817.
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| | journal = J Neuropsychiatry Clin Neurosci | volume = 14 | issue = 2
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| | pages = 223-36; discussion 222 | year = 2002 | pmid = 11983801
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| | url=http://neuro.psychiatryonline.org/cgi/content/full/14/2/223|format=Reproduced\
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| }}
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| </ref>
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| by the British physician [[James Parkinson]]. Parkinson's disease was then known as ''paralysis agitans'', the term "Parkinson's disease" being coined later by [[Jean-Martin Charcot]]. The underlying [[biochemical]] changes in the [[brain]] were identified in the 1950s due largely to the work of Swedish scientist [[Arvid Carlsson]], who later went on to win a [[Nobel Prize]]. [[L-dopa]] entered clinical practice in 1967,<ref>
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| {{cite journal
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| |author=Hornykiewicz O
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| |title=L-DOPA: from a biologically inactive amino acid to a successful therapeutic agent
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| |journal=Amino Acids
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| |volume=23
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| |issue=1-3
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| |pages=65-70
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| |year=2002
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| |pmid=12373520
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| |doi=10.1007/s00726-001-0111-9}}
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| </ref>
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| and the first study reporting improvements in patients with Parkinson's disease resulting from treatment with L-dopa was published in 1968.<ref>
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| {{cite journal
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| | author = Cotzias, G.
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| | title = L-Dopa for Parkinsonism. | journal = N Engl J Med
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| | volume = 278 | issue = 11 | pages = 630
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| | year = 1968 | id = PMID 5637779}}
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| </ref>
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| ==Symptoms== | | ==[[Parkinson's disease natural history|Natural History, Complications and Prognosis]]== |
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| Parkinson disease affects movement (motor symptoms). Typical other symptoms include disorders of mood, behavior, thinking, and sensation (non-motor symptoms). Individual patients' symptoms may be quite dissimilar and progression of the disease is also distinctly individual.
| | ==Diagnosis== |
| | | [[Parkinson's disease history and symptoms| History and Symptoms]] | [[Parkinson's disease physical examination | Physical Examination]] | [[Parkinson's disease laboratory findings|Laboratory Findings]] | [[Parkinson's disease CT|CT]] | [[Parkinson's disease MRI|MRI]] | [[Parkinson's disease other imaging findings|Other Imaging Findings]] | [[Parkinson's disease other diagnostic studies|Other Diagnostic Studies]] |
| ===Motor symptoms===
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| The [[cardinal symptom]]s are:
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| *''[[tremor]]'': normally 4-7 Hz tremor, maximal when the limb is at rest, and decreased with voluntary movement. It is typically unilateral at onset. This is the most apparent and well-known symptom, though an estimated 30% of patients have little perceptible tremor; these are classified as akinetic-rigid.
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| *''[[spasticity|rigidity]]'': stiffness; increased muscle tone. In combination with a resting tremor, this produces a ratchety, "cogwheel" rigidity when the limb is passively moved.
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| *''[[bradykinesia]]/[[akinesia]]'': respectively, slowness or absence of movement. Rapid, repetitive movements produce a dysrhythmic and decremental loss of amplitude. Also "dysdiadokinesia", which is the loss of ability to perform rapid ''alternating'' movements
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| *''[[postural instability]]'': failure of postural [[reflexes]], which leads to impaired balance and falls.
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| Other motor symptoms include:
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| *[[Gait]] and posture disturbances:
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| **Shuffling: gait is characterized by short steps, with feet barely leaving the ground, producing an audible shuffling noise. Small obstacles tend to trip the patient
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| **Decreased arm swing: a form of bradykinesia
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| **Turning "en bloc": rather than the usual twisting of the neck and trunk and pivoting on the toes, PD patients keep their neck and trunk rigid, requiring multiple small steps to accomplish a turn.
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| **Stooped, forward-flexed posture. In severe forms, the head and upper shoulders may be bent at a right angle relative to the trunk (camptocormia) <ref>{{cite journal |author=Lepoutre A, Devos D, Blanchard-Dauphin A, ''et al'' |title=A specific clinical pattern of camptocormia in Parkinson's disease |journal=J. Neurol. Neurosurg. Psychiatr. |volume=77 |issue=11 |pages=1229-34 |year=2006 |pmid=16735399}}</ref>.
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| **Festination: a combination of stooped posture, imbalance, and short steps. It leads to a gait that gets progressively faster and faster, often ending in a fall.
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| **Gait freezing: "freezing" is another word for akinesia, the inability to move. Gait freezing is characterized by inability to move the feet, especially in tight, cluttered spaces or when initiating gait.
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| **[[Dystonia]] (in about 20% of cases): abnormal, sustained, painful twisting muscle contractions, usually affecting the foot and ankle, characterized by toe flexion and foot inversion, interfering with gait. However, dystonia can be quite generalized, involving a majority of skeletal muscles; such episodes are acutely painful and completely disabling.
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| *Speech and swallowing disturbances
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| **Hypophonia: soft speech. Speech quality tends to be soft, hoarse, and monotonous. Some people with Parkinson's disease claim that their tongue is "heavy" or have [[cluttered speech]].<ref>{{cite book
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| | first=Michael
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| | middle=J
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| | last=Fox
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| | title= Lucky Man: A Memoir
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| | location =
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| | publisher= Hyperion
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| | isbn=0786888741
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| | pages=214
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| | year = 2003
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| }}</ref>.
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| **Festinating speech: excessively rapid, soft, poorly-intelligible speech.
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| **[[Drooling]]: most likely caused by a weak, infrequent swallow and stooped posture.
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| **Non-motor causes of speech/language disturbance in both expressive and receptive language: these include decreased verbal fluency and cognitive disturbance especially related to comprehension of emotional content of speech and of facial expression<ref>{{cite journal | author = Pell M | title = On the receptive prosodic loss in Parkinson's disease. | journal = Cortex | volume = 32 | issue = 4 | pages = 693-704 | year = 1996 | pmid = 8954247}}</ref>
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| **[[Dysphagia]]: impaired ability to swallow. Can lead to [[Pulmonary aspiration|aspiration]], [[pneumonia]].
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| *Other motor symptoms:
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| **[[fatigue (physical)|fatigue]] (up to 50% of cases);
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| **masked faces (a mask-like face also known as [[hypomimia]]), with infrequent [[blinking]];<ref>{{cite journal |author=Deuschl G, Goddemeier C |title=Spontaneous and reflex activity of facial muscles in dystonia, Parkinson's disease, and in normal subjects |journal=J. Neurol. Neurosurg. Psychiatr. |volume=64 |issue=3 |pages=320-4 |year=1998 |pmid=9527141 |url=http://jnnp.bmjjournals.com/cgi/content/full/64/3/320}}</ref>
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| **difficulty rolling in bed or rising from a seated position;
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| **[[micrographia (handwriting)|micrographia]] (small, cramped handwriting);
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| **impaired fine motor dexterity and [[motor coordination]];
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| **impaired gross motor coordination;
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| **Poverty of movement: overall loss of accessory movements, such as decreased arm swing when walking, as well as spontaneous movement.<!--[COULD THIS BE COMBINED W/ LOSS OF ARM SWING, WHICH IS ONE FORM OF ACCESSORY MOVEMENT?] -->
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| ===Non-motor symptoms===
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| ====Mood disturbances====
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| *Estimated prevalence rates of depression vary widely according to the population sampled and methodology used. Reviews of [[clinical depression|depression]] estimate its occurrence in anywhere from 20-80% of cases.<ref>{{cite journal | author = Lieberman A | title = Depression in Parkinson's disease -- a review. | journal = Acta Neurol Scand | volume = 113 | issue = 1 | pages = 1-8 | year = 2006|pmid = 16367891}}</ref> Estimates from community samples tend to find lower rates than from specialist centres. Most studies use self-report questionnaires such as the [[Beck Depression Inventory]], which may overinflate scores due to physical symptoms. Studies using diagnostic interviews by trained psychiatrists also report lower rates of depression.
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| *More generally, there is an increased risk for any individual with depression to go on to develop Parkinson's disease at a later date.<ref>{{cite journal | author = Ishihara L, Brayne C | title = A systematic review of depression and mental illness preceding Parkinson's disease. | journal = Acta Neurol Scand | volume = 113 | issue = 4 | pages = 211-20 | year = 2006 | pmid = 16542159}}</ref>
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| *70% of individuals with Parkinson's disease diagnosed with pre-existing depression go on to develop anxiety. 90% of Parkinson's disease patients with pre-existing anxiety subsequently develop depression; [[apathy]] or [[abulia]].
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| <!--VERY STRONG evidence of pre-emergence of either depression (up to ten years prior) or (anxiety) up to 20 years prior; essentially a prodome? CAN DOCUMENT-->
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| ====Cognitive disturbances====
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| *slowed reaction time; both voluntary and involuntary motor responses are significantly slowed.
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| *[[executive dysfunction]], characterized by difficulties in: differential allocation of attention, impulse control, set shifting, prioritizing, evaluating the salience of ambient data, interpreting social cues, and subjective time awareness. This complex is present to some degree in most Parkinson's patients; it may progress to:
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| *[[dementia]]: a later development in approximately 20-40% of all patients, typically starting with slowing of thought and progressing to difficulties with abstract thought, memory, and behavioral regulation. [[Hallucinations]], [[delusions]] and [[paranoia]] may develop.
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| *short term [[memory loss]]; [[procedural memory]] is more impaired than [[declarative memory]]. Prompting elicits improved recall.
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| *medication effects: some of the above cognitive disturbances are improved by dopaminergic medications, while others are actually worsened.<ref>{{cite journal |author=Frank MJ |title=Dynamic dopamine modulation in the basal ganglia: a neurocomputational account of cognitive deficits in medicated and nonmedicated Parkinsonism |journal=Journal of cognitive neuroscience |volume=17 |issue=1 |pages=51-72 |year=2005 |pmid=15701239 |doi=10.1162/0898929052880093}}</ref>
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| ====Sleep disturbances====
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| *Excessive daytime [[somnolence]]
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| *Initial, intermediate, and terminal [[insomnia]]
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| *Disturbances in [[Rapid eye movement sleep|REM]] sleep: disturbingly vivid dreams, and [[Rapid eye movement sleep|REM]] Sleep Disorder, characterized by acting out of dream content - can occur years prior to diagnosis
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| ====Sensation disturbances====
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| *impaired visual [[contrast sensitivity]], spatial reasoning, [[color|colour]] discrimination, convergence insufficiency (characterized by [[double vision]]) and [[oculomotor control]]
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| *[[dizziness]] and fainting; usually attributable orthostatic hypotension, a failure of the autonomous nervous system to adjust blood pressure in response to changes in body position
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| *impaired [[proprioception]] (the awareness of bodily position in three-dimensional space)
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| *reduction or loss of sense of [[olfaction|smell]] (microsmia or [[anosmia]]) - can occur years prior to diagnosis,
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| *[[Pain and nociception|pain]]: neuropathic, muscle, joints, and tendons, attributable to tension, dystonia, rigidity, joint stiffness, and injuries associated with attempts at accommodation
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| ====Autonomic disturbances====
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| *oily skin and [[seborrheic dermatitis]]<ref>{{cite journal |author=Gupta A, Bluhm R |title=Seborrheic dermatitis |journal=Journal of the European Academy of Dermatology and Venereology : JEADV |volume=18 |issue=1 |pages=13-26; quiz 19-20 |year=2004 |pmid=14678527}}</ref>
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| *[[urinary incontinence]], typically in later disease progression
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| *[[nocturia]] (getting up in the night to pass urine) - up to 60% of cases
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| *[[constipation]] and [[gastric]] dysmotility that is severe enough to endanger comfort and even health
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| *altered sexual function: characterized by profound impairment of sexual arousal, behavior, orgasm, and drive is found in mid and late Parkinson disease. Current data addresses male sexual function almost exclusively
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| *[[weight loss]], which is significant over a period of ten years - 8% of body [[weight loss|weight lost]] compared with 1% in a control group.
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| == Diagnosis == | |
| [[Image:PET scan Parkinson's Disease.jpg|thumb|200px|18F PET scan shows decreased dopamine activity in the [[basal ganglia]], a pattern which aids in diagnosing Parkinson's disease.]] | |
| There are currently no blood or laboratory tests that have been proven to help in diagnosing PD. Therefore the diagnosis is based on medical history and a neurological examination. The disease can be difficult to diagnose accurately. The [[Unified Parkinson's Disease Rating Scale]] is the primary clinical tool used to assist in diagnosis and determine severity of PD. Indeed, only 75% of clinical diagnoses of PD are confirmed at autopsy.<ref>{{cite journal | author = Gelb D, Oliver E, Gilman S | title = Diagnostic criteria for Parkinson disease. | journal = Arch Neurol | volume = 56 | issue = 1 | pages = 33-9 | year = 1999 | pmid = 9923759}}</ref> Early signs and symptoms of PD may sometimes be dismissed as the effects of normal aging. The physician may need to observe the person for some time until it is apparent that the symptoms are consistently present. Usually doctors look for shuffling of feet and lack of swing in the arms. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases. However, CT and MRI brain scans of people with PD usually appear normal.
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| == Descriptive epidemiology==
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| Parkinson's disease is widespread, with a prevalence estimated between 100 and 250 cases per 100,000 in North America; and was 1.7 per hundred (95% CI 1.5–1.9) in China (for those aged ≥65 years).<ref>{{cite journal |author=Zhang ZX, Roman GC, Hong Z, ''et al'' |title=Parkinson's disease in China: prevalence in Beijing, Xian, and Shanghai |journal=Lancet |volume=365 |issue=9459 |pages=595–7 |year=2005 |pmid=15708103 |doi=10.1016/S0140-6736(05)17909-4}}</ref> Because prevalence rates can be affected by socio-ecomically driven differences in survival as well as biased by survey technique problems,<ref>{{cite journal |author=Bermejo F, Gabriel R, Vega S, Morales JM, Rocca WA, Anderson DW |title=Problems and issues with door-to-door, two-phase surveys: an illustration from central Spain |journal=Neuroepidemiology |volume=20 |issue=4 |pages=225–31 |year=2001 |pmid=11684897 |doi=}}</ref> incidence is a more sensitive indicator: rates to a high of 20.5 per 100,000 in the U.S.A. <ref>{{cite journal | author = Rajput | title = Epidemiology of Parkinson's disease | journal = Can J Neurol Sci. | volume = 11 | issue = 1 | pages = 156–159 | year = 1984 | pmid = 6713314}}</ref> A study carried out in northern California observed an age and sex corrected incidence.<ref name="VanDenEeden2003">{{cite journal | author = Van Den Eeden S, Tanner C, Bernstein A, Fross R, Leimpeter A, Bloch D, Nelson L | title = Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. | journal = Am J Epidemiol | volume = 157 | issue = 11 | pages = 1015–22 | year = 2003 | pmid = 12777365}}</ref>
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| Cases of PD are reported at all ages, though it is uncommon in people younger than 40. The average age at which symptoms begin in the U.S.A. is 58–60; it is principally a disease of the elderly. It occurs in all parts of the world, but appears to be more common in people of European ancestry than in those of African ancestry. Those of East Asian ancestry have an intermediate risk. It is more common in rural than urban areas and men are affected more often than women in most countries.
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| ==Related diseases==
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| There are other disorders that are called ''[[Parkinson plus syndrome|Parkinson-plus diseases]]''. These include:
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| * [[Multiple system atrophy]] (MSA)
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| * Progressive supranuclear palsy (PSP)
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| * Corticobasal degeneration (CBD)
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| Some people include dementia with Lewy bodies (DLB) as one of the 'Parkinson-plus' syndromes. Although idiopathic Parkinson's disease patients also have Lewy bodies in their brain tissue, the distribution is denser and more widespread in DLB. Even so, the relationship between Parkinson disease, Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB) might be most accurately conceptualized as a spectrum, with a discrete area of overlap between each of the three disorders. The natural history and role of Lewy bodies is very little understood.
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| Patients often begin with typical Parkinson's disease symptoms which persist for some years; these Parkinson-plus diseases can only be diagnosed when other symptoms become apparent with the passage of time. These Parkinson-plus diseases usually progress more quickly than typical ideopathic Parkinson disease. The usual anti-Parkinson's medications are typically either less effective or not effective at all in controlling symptoms; patients may be exquisitely sensitive to neuroleptic medications like [[haloperidol]]. Additionally, the cholinesterase inhibiting medications have shown preliminary efficacy in treating the cognitive, psychiatric, and behavioral aspects of the disease, so correct differential diagnosis is important.
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| [[Wilson's disease]] (hereditary copper accumulation) may present with parkinsonistic features; young patients presenting with parkinsonism may be screened for this rare condition. [[Essential tremor]] is often mistaken for Parkinson's disease but usually lacks all features besides tremor.
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| [[Torsion dystonia]] is another disease related to Parkinson's disease.
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| ==Pathology==
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| The direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder. The lack of [[dopamine]] results in increased inhibition of the ventral lateral nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to [[hypokinesia]].
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| There are four major dopamine pathways in the brain; the nigrostriatal pathway, referred to above, mediates movement and is the most conspicuously affected in early Parkinson's disease. The other pathways are the mesocortical, the mesolimbic, and the tuberoinfundibular. These pathways are associated with, respectively: volition and emotional responsiveness; desire, initiative, and reward; and sensory processes and maternal behavior. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinson's disease.
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| The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein [[alpha-synuclein]] bound to ubiquitin in the damaged cells. The [[alpha-synuclein]]-ubiquitin complex cannot be directed to the proteosome. This [[protein]] accumulation forms proteinaceous cytoplasmic inclusions called [[Lewy bodies]]. Latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles — the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rab1 may reverse this defect caused by alpha-synuclein in animal models.<ref>"Parkinson's Disease Mechanism Discovered," [http://www.hhmi.org/news/lindquist20060622.html HHMI Research News] June 22, 2006.</ref>
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| Excessive accumulations of iron, which are toxic to nerve cells, are also typically observed in conjunction with the protein inclusions. Iron and other transition metals such as copper bind to [[neuromelanin]] in the affected neurons of the [[substantia nigra]]. So, [[neuromelanin]] may be acting as a protective agent. Alternately, neuromelanin (an electronically active semiconductive polymer) may play some other role in neurons.<ref>{{cite journal | author = McGinness J, Corry P, Proctor P | title = Amorphous semiconductor switching in melanins. | journal = Science | volume = 183 | issue = 127 | pages = 853-5 | year = 1974 | pmid = 4359339 | url=http://www.drproctor.com/os/amorphous.htm | format=Reprint}}</ref> That is, coincidental excessive accumulation of transition metals, etc. on [[neuromelanin]] may figure in the differential dropout of pigmented neurons in Parkinsonism. The most likely mechanism is generation of [[reactive oxygen species]].<ref name="Jenner1998">{{cite journal | author = Jenner P | title = Oxidative mechanisms in nigral cell death in Parkinson's disease. | journal = Mov Disord | volume = 13 Suppl 1 | issue = | pages = 24-34 | year =1998 | pmid = 9613715}}</ref>
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| Iron induces aggregation of synuclein by oxidative mechanisms.<ref>{{cite journal | author = Kaur D, Andersen J | title = Ironing out Parkinson's disease: is therapeutic treatment with iron chelators a real possibility? | journal = Aging Cell | volume = 1 | issue = 1 | pages = 17-21 | year = 2002 | pmid = 12882349 | url=http://www.blackwell-synergy.com/doi/pdf/10.1046/j.1474-9728.2002.00001.x | format=PDF}}</ref> Similarly, dopamine and the byproducts of dopamine production enhance alpha-synuclein aggregation. The precise mechanism whereby such aggregates of alpha-synuclein damage the cells is not known. The aggregates may be merely a normal reaction by the cells as part of their effort to correct a different, as-yet unknown, insult. Based on this mechanistic hypothesis, a [[Genetically modified organism|transgenic mouse model]] of Parkinson's has been generated by introduction of human wild-type α-synuclein into the mouse genome under control of the [[Platelet-derived growth factor|platelet-derived-growth factor]]-β promoter.<ref>{{cite journal |author=Masliah E, Rockenstein E, Veinbergs I, ''et al'' |title=Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders |journal=Science |volume=287 |issue=5456 |pages=1265-9 |year=2000 |pmid=10678833 |doi=}}</ref>
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| <gallery>
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| Image:DA-loops in PD.jpg|Dopaminergic pathways of the human brain in normal condition (left) and Parkinson's disease (right). Red Arrows indicate suppression of the target, blue arrows indicate stimulation of target structure.
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| </gallery>
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| The symptoms of Parkinson's disease result from the loss of pigmented [[dopamine]]-secreting (dopaminergic) cells, secreted by the same cells, in the [[substantia nigra|pars compacta]] region of the [[substantia nigra]] (literally "black substance"). These neurons project to the [[striatum]] and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the [[direct pathway]] and excitation of the [[indirect pathway]].
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| ==Causes of Parkinson's disease==
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| Most people with Parkinson's disease are described as having [[idiopathic]] Parkinson's disease (having no specific cause). There are far less common causes of Parkinson's disease including genetic, toxins, head trauma, and drug-induced Parkinson's disease.
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| ===Genetic===
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| In recent years, a number of specific genetic mutations causing Parkinson's disease have been discovered, including in certain populations ([[Contursi]], Italy). These account for a small minority of cases of Parkinson's disease. Somebody who has Parkinson's disease is more likely to have relatives that also have Parkinson's disease. However, this does not mean that the disorder has been passed on genetically.
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| Genetic forms that have been identified include:
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| :''external links in this section are to [[OMIM]]''
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| {| class="wikitable"
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| | '''Type''' || '''OMIM''' || '''[[Locus (genetics)|Locus]]''' || '''Details'''
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| | ''PARK1'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=168601 OMIM #168601] || 4q21 || caused by mutations in the ''[[SNCA]]'' gene, which codes for the [[protein]] [[alpha-synuclein]]. PARK1 causes [[autosomal dominant]] Parkinson disease. So-called ''PARK4'' ([http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605543 OMIM #605543]) is probably caused by triplication of ''SNCA''.<ref>{{cite journal |author=Singleton AB, Farrer M, Johnson J, ''et al'' |title=alpha-Synuclein locus triplication causes Parkinson's disease |journal=Science |volume=302 |issue=5646 |pages=841 |year=2003 |pmid=14593171 |doi=10.1126/science.1090278}}</ref>
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| | ''PARK2'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602544 OMIM *602544] || 6q25.2-q27 || caused by mutations in protein [[Parkin (ligase)|parkin]]. Parkin mutations may be one of the most common known genetic causes of early-onset Parkinson disease. In one study, of patients with onset of Parkinson disease prior to age 40 (10% of all PD patients), 18% had parkin mutations, with 5% [[homozygous]] mutations.<ref>{{cite journal | author=Poorkaj P ''et al.'' | title=''parkin'' mutation analysis in clinic patients with early-onset Parkinson's disease | journal=American Journal of Medical Genetics Part A | year=2004 | volume=129A |
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| issue=1 | pages= 44–50 | url=http://www3.interscience.wiley.com/cgi-bin/abstract/109062750/ABSTRACT?CRETRY=1&SRETRY=0}}</ref> Patients with an [[autosomal recessive]] family history of parkinsonism are much more likely to carry parkin mutations if age at onset is less than 20 (80% vs. 28% with onset over age 40).<ref>{{cite journal | author=Ebba Lohmann ''et al.'' | title=How much phenotypic variation can be attributed to parkin genotype? | journal=Annals of Neurology | year=2003 | volume=54 | issue=2 | pages= 176–185|url=http://www3.interscience.wiley.com/cgi-bin/abstract/104536414/ABSTRACT | pmid = 12891670}}</ref>Patients with [[parkin]] mutations (PARK2) do not have Lewy bodies. Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age.
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| | ''PARK3'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602404 OMIM %602404] || 2p13 || autosomal dominant, only described in a few kindreds.
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| | ''PARK5'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191342 OMIM +191342] || 4p14 || caused by mutations in the ''UCHL1'' gene which codes for the protein [[ubiquitin carboxy-terminal hydrolase L1]]
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| | ''PARK6'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605909 OMIM #605909] || 1p36 || caused by mutations in ''PINK1'' ([http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=605909 OMIM *608309]) which codes for the protein [[PTEN-induced putative kinase 1]].
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| | ''[[PARK7]]'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606324 OMIM #606324] || 1p36 || caused by mutations in [[PARK7|DJ-1]] ([http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602533 OMIM 602533])
| |
| |-
| |
| | ''PARK8'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607060 OMIM #607060] || 12q12 || caused by mutations in [[LRRK2]] which codes for the protein [[dardarin]]. ''In vitro'', mutant LRRK2 causes protein aggregation and cell death, possibly through an interaction with parkin.<ref>{{cite journal | author=Smith WW ''et al.'' | title=Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration | journal=[[Proceedings of the National Academy of Sciences of the United States of America]] | year=2005 | volume=102 | issue=51 | pages= 18676–18681 | url=http://www.pnas.org/cgi/content/abstract/102/51/18676 | pmid = 16352719}}</ref> LRRK2 mutations, of which the most common is G2019S, cause autosomal dominant Parkinson disease, with a [[penetrance]] of nearly 100% by age 80.<ref>{{cite journal |author=Kachergus J, Mata IF, Hulihan M, ''et al'' |title=Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations |journal=Am. J. Hum. Genet. |volume=76 |issue=4 |pages=672-80 |year=2005 |pmid=15726496 |doi=10.1086/429256}}</ref> G2019S is the most common known genetic cause of Parkinson disease, found in 1-6% of U.S. and European PD patients.<ref>{{cite journal |author=Brice A |title=Genetics of Parkinson's disease: LRRK2 on the rise |journal=Brain |volume=128 |issue=Pt 12 |pages=2760-2 |year=2005 |url=http://brain.oxfordjournals.org/cgi/content/extract/128/12/2760 |pmid=16311269 |doi=10.1093/brain/awh676}}
| |
| </ref> It is especially common in Ashkenazi Jewish patients, with a prevalence of 29.7% in familial cases and 13.3% in sporadic.<ref>{{cite journal | author = Ozelius L, Senthil G, Saunders-Pullman R, ''et al'' | title = LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. | journal = N Engl J Med | volume = 354 | issue = 4 | pages = 424-5 | year = 2006 | pmid = 16436782}}</ref>
| |
| |-
| |
| | ''PARK9'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606693 OMIM #606693] || 1p36 || Caused by mutations in the ''ATP13A2'' gene, and also known as Kufor-Rakeb Syndrome. PARK9 may be allelic to PARK6.
| |
| |-
| |
| | ''PARK10'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606852 OMIM %606852] || 1p || -
| |
| |-
| |
| | ''PARK11'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607688 OMIM %607688] || 2q36-37 || However, this gene locus has conflicting data, and may not have significance.
| |
| |-
| |
| | ''PARK12'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300557 OMIM %300557] || Xq21-q25 || -
| |
| |-
| |
| | ''PARK13'' || [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610297 OMIM #610297] || 2p12 || Caused by mutations in the ''HTRA2'' ([[HtrA serine peptidase 2]]) gene.
| |
| |}
| |
| | |
| ===Toxins===
| |
| | |
| One theory holds that the disease may result in many or even most cases from the combination of a genetically determined vulnerability to environmental [[toxin]]s along with exposure to those toxins.<ref>{{cite journal |author=Di Monte DA, Lavasani M, Manning-Bog AB |title=Environmental factors in Parkinson's disease |journal=Neurotoxicology |volume=23 |issue=4-5 |pages=487-502 |year=2002 |pmid=12428721 |doi=}}</ref> This hypothesis is consistent with the fact that Parkinson's disease is not distributed homogeneously throughout the population: rather, its incidence varies geographically. It would appear that incidence varies by time as well, for although the later stages of untreated PD are distinct and readily recognizable, the disease was not remarked upon until the beginnings of the Industrial Revolution, and not long thereafter become a common observation in clinical practice. The toxins most strongly suspected at present are certain [[pesticide]]s and transition-series metals such as manganese or iron, especially those that generate [[reactive oxygen species]],<ref name="Jenner1998">{{cite journal |author=Jenner P |title=Oxidative mechanisms in nigral cell death in Parkinson's disease |journal=Mov. Disord. |volume=13 Suppl 1 |issue= |pages=24-34 |year=1998 |pmid=9613715 |doi=}}</ref><ref>{{cite journal |author=Chiueh CC, Andoh T, Lai AR, Lai E, Krishna G |title=Neuroprotective strategies in Parkinson's disease: protection against progressive nigral damage induced by free radicals |journal=Neurotoxicity research |volume=2 |issue=2-3 |pages=293-310 |year=2000 |pmid=16787846 |doi=}}</ref>
| |
| and or bind to [[neuromelanin]], as originally suggested by G.C. Cotzias.<ref>{{cite journal | author = Cotzias G | title = Manganese, melanins and the extrapyramidal system. | journal = J Neurosurg | volume = 24 | issue = 1 | pages = Suppl:170-80 | year = 1966 | pmid = 4955707}}</ref><ref>{{cite journal | author = Barbeau A | title = Manganese and extrapyramidal disorders (a critical review and tribute to Dr. George C. Cotzias). | journal = Neurotoxicology | volume = 5 | issue = 1 | pages = 13-35 | year = 1984 | pmid = 6538948}}</ref>. In the Cancer Prevention Study II Nutrition Cohort, a longitudinal investigation, individuals who were exposed to pesticides had a 70% higher incidence of PD than individuals who were not exposed<ref>{{cite journal | author = Ascherio A, Chen H, Weisskopf M, ''et al'' | title = Pesticide exposure and risk for Parkinson's disease. | journal = Ann Neurol | volume = 60 | issue = 2 | pages = 197-203 | year = 2006 | pmid = 16802290}}</ref>.
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| | |
| [[MPTP]] is used as a model for Parkinson's as it can rapidly induce parkinsonian symptoms in human beings and other animals, of any age. MPTP was notorious for a string of Parkinson's disease cases in California in 1982 when it contaminated the illicit production of the synthetic opiate [[MPPP]]. Its toxicity likely comes from generation of [[reactive oxygen species]] through tyrosine hydroxylation.<ref>{{cite journal | author = Chiueh C, Wu R, Mohanakumar K, Sternberger L, Krishna G, Obata T, Murphy D | title = ''In vivo'' generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia. | journal = Ann N Y Acad Sci | volume = 738 | issue = | pages = 25-36 | year = 1994 |pmid = 7832434}}</ref>
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| | |
| Other toxin-based models employ PCBs,<ref>{{cite news | |
| |first=Leslie
| |
| |last=Orr
| |
| |title=PCBs, fungicide open brain cells to Parkinson's assault
| |
| |date=February 10, 2005
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| |publisher=[[Medical News Today]]
| |
| |url=http://www.medicalnewstoday.com/medicalnews.php?newsid=19791
| |
| }}</ref> [[paraquat]]<ref>{{cite journal |author=Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA |title=The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein |journal=J. Biol. Chem. |volume=277 |issue=3 |pages=1641-4 |year=2002 |pmid=11707429 |doi=10.1074/jbc.C100560200 | url=http://www.jbc.org/cgi/content/full/277/3/1641}}</ref> (a herbicide) in combination with maneb (a fungicide)<ref>{{cite journal |author=Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slechta DA |title=The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson's disease |journal=J. Neurosci. |volume=20 |issue=24 |pages=9207-14 |year=2000 |pmid=11124998 |url=http://www.jneurosci.org/cgi/content/full/20/24/9207
| |
| }}</ref> [[rotenone]]<ref>{{cite journal |author=Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT |title=Chronic systemic pesticide exposure reproduces features of Parkinson's disease |journal=Nat. Neurosci. |volume=3 |issue=12 |pages=1301-6 |year=2000 |pmid=11100151 |doi=10.1038/81834}}</ref> (an insecticide), and specific organochlorine pesticides including dieldrin<ref>{{cite journal |author=Kitazawa M, Anantharam V, Kanthasamy AG |title=Dieldrin-induced oxidative stress and neurochemical changes contribute to apoptopic cell death in dopaminergic cells |journal=Free Radic. Biol. Med. |volume=31 |issue=11 |pages=1473-85 |year=2001 |pmid=11728820 |url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T38-44HSN76-P&_coverDate=12%2F01%2F2001&_alid=373422978&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4940&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=5a104ac89bd7948e14863371142a639a
| |
| }}</ref> and lindane.<ref>{{cite journal |author=Corrigan FM, Wienburg CL, Shore RF, Daniel SE, Mann D |title=Organochlorine insecticides in substantia nigra in Parkinson's disease |journal=J. Toxicol. Environ. Health Part A |volume=59 |issue=4 |pages=229-34 |year=2000 |pmid=10706031
| |
| |url=http://journalsonline.tandf.co.uk/openurl.asp?genre=article&eissn=1087-2620&volume=59&issue=4&spage=229
| |
| }}</ref> Numerous studies have found an increase in PD in persons who consume rural well water; researchers theorize that water consumption is a proxy measure of pesticide exposure. In agreement with this hypothesis are studies which have found a dose-dependent an increase in PD in persons exposed to agricultural chemicals.
| |
| | |
| ===Head trauma===
| |
| Past episodes of head trauma are reported more frequently by sufferers than by others in the population.<ref name=Bower>{{cite journal |author=Bower JH, Maraganore DM, Peterson BJ, McDonnell SK, Ahlskog JE, Rocca WA |title=Head trauma preceding PD: a case-control study |journal=Neurology |volume=60 |issue=10 |pages=1610-5 |year=2003 |pmid=12771250 | url=http://www.neurology.org/cgi/content/abstract/60/10/1610}}</ref><ref>{{cite journal |author=Stern M, Dulaney E, Gruber SB, ''et al'' |title=The epidemiology of Parkinson's disease. A case-control study of young-onset and old-onset patients |journal=Arch. Neurol. |volume=48 |issue=9 |pages=903-7 |year=1991 |pmid=1953412 url=http://archneur.ama-assn.org/cgi/content/abstract/48/9/903}}</ref><ref name="Uryu2003">{{cite journal |author=Uryu K, Giasson BI, Longhi L, ''et al'' |title=Age-dependent synuclein pathology following traumatic brain injury in mice |journal=Exp. Neurol. |volume=184 |issue=1 |pages=214-24 |year=2003 |pmid=14637093 |doi=}}</ref>
| |
| A methodologically strong recent study<ref name=Bower/> found that those who have experienced a head injury are four times more likely to develop Parkinson’s disease than those who have never suffered a head injury. The risk of developing Parkinson’s increases eightfold for patients who have had head trauma requiring hospitalization, and it increases 11-fold for patients who have experienced severe head injury. The authors comment that since head trauma is a rare event, the contribution to PD incidence is slight. They express further concern that their results may be biased by recall, i.e., the PD patients because they reflect upon the causes of their illness, may remember head trauma better than the non-ill control subjects. These limitations were overcome recently by Tanner and colleagues,<ref>{{cite journal |author=Goldman SM, Tanner CM, Oakes D, Bhudhikanok GS, Gupta A, Langston JW |title=Head injury and Parkinson's disease risk in twins |journal=Ann. Neurol. |volume=60 |issue=1 |pages=65-72 |year=2006 |pmid=16718702 |doi=10.1002/ana.20882}}</ref> who found a similar risk of 3.8, with increasing risk associated with more severe injury and hospitalization.
| |
| | |
| ===Drug-induced===
| |
| | |
| [[Antipsychotics]], which are used to treat [[schizophrenia]] and psychosis, can induce the symptoms of Parkinson's disease (or parkinsonism) by lowering dopaminergic activity. Due to feedback inhibition, L-dopa can also eventually cause the symptoms of Parkinson's disease that it initially relieves. Dopamine agonists can also eventually contribute to Parkinson's disease symptoms by decreasing the sensitivity of dopamine receptors.
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|
| |
|
| ==Treatment== | | ==Treatment== |
| | | [[Parkinson's disease medical therapy|Medical Therapy]] | [[Parkinson's disease surgery|Surgery]] | [[Parkinson's disease primary prevention|Primary Prevention]] | [[Parkinson's disease secondary prevention|Secondary Prevention]] | [[Parkinson's disease cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Parkinson's disease future or investigational therapies|Future or Investigational Therapies]] |
| Parkinson's disease is a chronic disorder that requires broad-based management including patient and family education, support group services, general wellness maintenance, exercise, and nutrition. At present, there is no cure for PD, but medications or surgery can provide relief from the symptoms.
| |
| | |
| === Levodopa ===
| |
| | |
| <gallery>
| |
| Image:Stalevo.jpg|Stalevo for treatment of Parkinson's disease
| |
| </gallery>
| |
| | |
| The most widely used form of treatment is [[L-dopa]] in various forms. L-dopa is transformed into dopamine in the dopaminergic neurons by L-aromatic amino acid decarboxylase (often known by its former name dopa-decarboxylase). However, only 1-5% of L-DOPA enters the dopaminergic neurons. The remaining L-DOPA is often metabolised to dopamine elsewhere, causing a wide variety of side effects. Due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa, and so eventually becomes counterproductive.
| |
| | |
| [[Carbidopa]] and [[benserazide]] are dopa decarboxylase inhibitors. They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are generally given as combination preparations of [[carbidopa/levodopa]] (co-careldopa) (e.g. Sinemet, Parcopa) and [[benserazide|benserazide/levodopa]] (co-beneldopa) (e.g. Madopar). There are also controlled release versions of Sinemet and Madopar that spread out the effect of the L-dopa. Duodopa is a combination of levodopa and carbidopa, dispersed as a viscous gel. Using a patient-operated portable pump, the drug is continuously delivered via a tube directly into the upper small intestine, where it is rapidly absorbed.
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| | |
| [[Tolcapone]] inhibits the [[COMT]] enzyme, thereby prolonging the effects of L-dopa, and so has been used to complement L-dopa. However, due to its possible side effects such as liver failure, it's limited in its availability.
| |
| | |
| A similar drug, [[entacapone]], has similar efficacy and has not been shown to cause significant alterations of liver function. A recent follow-up study by Cilia and colleagues<ref name=TNcilia>
| |
| {{cite web | author=R. Cilia ''et al.''|year=2006
| |
| | title=Long-term Efficacy of Entacapone in Patients with
| |
| Parkinson's Disease and Motor Fluctuations - A Six-Year
| |
| Clinical Follow-Up Study
| |
| |url=http://www.touchneurology.com/articles.cfm?article_id=5728&level=2}}
| |
| </ref>
| |
| looked at the clinical effects of long-term administration of entacapone, on motor performance and pharmacological compensation, in advanced PD patients with motor fluctuations: 47 patients with advanced PD and motor fluctuations were followed for six years from the first prescription of entacapone and showed a stabilization of motor conditions, reflecting entacapone can maintain adequate inhibition of COMT over time.<ref name=TNcilia/>
| |
| ''[[Mucuna pruriens]]'', is a natural source of therapeutic quantities of L-dopa, and has been under some investigation<ref>{{cite journal |author=Katzenschlager R, Evans A, Manson A, ''et al'' |title=Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study |journal=J. Neurol. Neurosurg. Psychiatr. |volume=75 |issue=12 |pages=1672-7 |year=2004 |pmid=15548480 |doi=10.1136/jnnp.2003.028761}}</ref>
| |
| | |
| === Dopamine agonists ===
| |
| The dopamine-agonists [[bromocriptine]], [[pergolide]], [[pramipexole]], [[ropinirole]] , [[cabergoline]], [[apomorphine]], and [[lisuride]], are moderately effective. These have their own side effects including those listed above in addition to somnolence, hallucinations and /or insomnia. Several forms of dopamine agonism have been linked with a markedly increased risk of problem gambling. Dopamine agonists initially act by stimulating some of the dopamine receptors. However, they cause the dopamine receptors to become progressively less sensitive, thereby eventually increasing the symptoms.
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| | |
| Dopamine agonists can be useful for patients experiencing on-off fluctuations and dyskinesias as a result of high doses of L-dopa. Apomorphine can be administered via subcutaneous injection using a small pump which is carried by the patient. A low dose is automatically administered throughout the day, reducing the fluctuations of motor symptoms by providing a steady dose of dopaminergic stimulation. After an initial "apomorphine challenge" in hospital to test its effectiveness and brief patient and caregiver, the primary caregiver (often a spouse or partner) takes over maintenance of the pump. The injection site must be changed daily and rotated around the body to avoid the formation of [[Nodule (medicine)|nodules]]. Apomorphine is also available in a more acute dose as an [[autoinjector]] pen for emergency doses such as after a fall or first thing in the morning.
| |
| | |
| === MAO-B inhibitors ===
| |
| [[Selegiline]] and [[rasagiline]] reduce the symptoms by inhibiting monoamine oxidase-B (MAO-B), which inhibits the breakdown of dopamine secreted by the dopaminergic neurons. Metabolites of selegiline include L-amphetamine and L-methamphetamine (not to be confused with the more notorious and potent dextrorotary isomers). This might result in side effects such as insomnia. Use of L-dopa in conjunction with selegiline has increased mortality rates that have not been effectively explained. Another side effect of the combination can be stomatitis. One report raised concern about increased mortality when MAO-B inhibitors were combined with L-dopa;<ref>{{cite journal | author = Thorogood M, Armstrong B, Nichols T, Hollowell J | title = Mortality in people taking selegiline: observational study. | journal = BMJ | volume = 317 | issue = 7153 | pages = 252-4 | year = 1998 | pmid = 9677215}}</ref> however subsequent studies have not confirmed this finding.<ref>{{cite journal | author = Marras C, McDermott M, Rochon P, Tanner C, Naglie G, Rudolph A, Lang A | title = Survival in Parkinson disease: thirteen-year follow-up of the DATATOP cohort. | journal = Neurology | volume = 64 | issue = 1 | pages = 87-93 | year = 2005 | pmid = 15642909}}</ref> Unlike other non selective [[monoamine oxidase inhibitors]], tyramine-containing foods do not cause a hypertensive crisis. | |
| | |
| ===Speech therapies===
| |
| The most widely practiced treatment for the speech disorders associated with Parkinson's disease is Lee Silverman Voice Treatment (LSVT). LSVT focuses on increasing vocal loudness.<ref>"What is LSVT?" http://www.lsvt.org/main_site.htm</ref>
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| | |
| A study found that an electronic device providing frequency-shifted auditory feedback (FAF) improved the clarity of Parkinson's patients' speech.<ref>Lowit, A., Brendel, B. "The response of patients with Parkinson's Disease to DAF and FSF," [http://www.stammering.org/sr.html Stammering Research] April 2004.</ref>
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| | |
| ===Physical exercise===
| |
| Regular physical exercise and/or therapy, including in forms such as yoga, tai chi, and dance can be beneficial to the patient for maintaining and improving mobility, flexibility, balance and a range of motion. Physicians and physical therapists often recommend basic exercises, such as bringing the toes up with every step, carrying a bag with weight to decrease the bend having on one side, and practicing chewing hard and move the food around the mouth.<ref>Garg, R and Lakhan, S. [http://brainblogger.com/2006/08/13/parkinsons-disease-pharmaceutical-and-physical-therapies/ Parkinson's Disease - Pharmaceutical and Physical Therapies]. [http://brainblogger.com ''GNIF Brain Blogger'']. August, 2006.</ref>
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| | |
| ===Surgery and deep brain stimulation===
| |
| [[Image:Parkinson surgery.jpg|thumb|200px|Illustration showing an electrode placed deep seated in the brain]]
| |
| Treating Parkinson's disease with surgery was once a common practice, but after the discovery of levodopa, surgery was restricted to only a few cases. Studies in the past few decades have led to great improvements in surgical techniques, and surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient.
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| | |
| [[Deep brain stimulation]] is presently the most used surgical means of treatment, but other surgical therapies that have shown promise include surgical lesion of the [[subthalamic nucleus]]<ref>{{cite journal |author=Guridi J, Obeso JA |title=The subthalamic nucleus, hemiballismus and Parkinson's disease: reappraisal of a neurosurgical dogma |journal=Brain |volume=124 |issue=Pt 1 |pages=5-19 |year=2001 |pmid=11133783 | url=http://brain.oxfordjournals.org/cgi/content/full/124/1/5}}</ref> and of the internal segment of the [[globus pallidus]], a procedure known as [[pallidotomy]].<ref>{{cite journal |author=Fukuda M, Kameyama S, Yoshino M, Tanaka R, Narabayashi H |title=Neuropsychological outcome following pallidotomy and thalamotomy for Parkinson's disease |journal=Stereotactic and functional neurosurgery |volume=74 |issue=1 |pages=11-20 |year=2000 |pmid=11124660 |doi=}}</ref>
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| | |
| ===Methods undergoing evaluation===
| |
| ====Gene therapy====
| |
| Currently under investigation is gene therapy. This involves using a harmless virus to shuttle a gene into a part of the brain called the subthalamic nucleus (STN). The gene used leads to the production of an enzyme called glutamic acid decarboxylase ([[Glutamate decarboxylase|GAD]]), which catalyses the production of a [[neurotransmitter]] called [[GABA]].<!--
| |
| | |
| --><ref name="pmid17586305">{{cite journal |author=Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P, Lawlor PA, Bland RJ, Young D, Strybing K, Eidelberg D, During MJ |title=Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial |journal=Lancet |volume=369 |issue=9579 |pages=2097-105 |year=2007 |pmid=17586305 |doi=10.1016/S0140-6736(07)60982-9}}</ref><!--
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| --> GABA acts as a direct inhibitor on the overactive cells in the STN.
| |
| | |
| [[GDNF]] infusion involves the infusion of GDNF (glial-derived neurotrophic factor) into the basal ganglia using surgically implanted catheters. Via a series of biochemical reactions, GDNF stimulates the formation of L-dopa. GDNF therapy is still in development. | |
| | |
| Implantation of stem cells genetically engineered to produce dopamine or stem cells that transform into dopamine-producing cells has already started being used. These could not constitute cures because they do not address the considerable loss of activity of the dopaminergic neurons. Initial results have been unsatifactory, with patients still retaining their drugs and symptoms.
| |
| | |
| ==== Neuroprotective treatments ====
| |
| [[Neuroprotective]] treatments are at the forefront of PD research, but are still under clinical scrutiny<ref> {{cite journal| author=Bonuccelli U,
| |
| Del Dotto P| title= New pharmacologic horizons in the treatment of Parkinson disease | journal=Neurology | year=2006 | volume=67 | issue=2 | pages= 30-38}}</ref>. These agents could protect neurons from cell death induced by disease presence resulting in a slower pregression of disease. Agents currently under investigation as neuroprotective agents include apoptotic drugs (CEP 1347 and CTCT346), lazaroids, bioenergetics, antiglutamatergic agents and dopamine receptors<ref>{{cite journal |author=Djaldetti R, Melamed E |title=New drugs in the future treatment of Parkinson's disease |journal=J. Neurol. |volume=249 Suppl 2 |issue= |pages=II30-5 |year=2002 |pmid=12375061 |doi=10.1007/s00415-002-1206-2}}</ref>. Clinically evaluated neuroprotective agents are the monoamine oxidase inhibitors selegiline<ref name=PSG_1993>{{cite journal |author= |title=Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group |journal=N. Engl. J. Med. |volume=328 |issue=3 |pages=176-83 |year=1993 |pmid=8417384 |doi=}}</ref> and rasagiline, dopamine agonists, and the complex I mitochondrial fortifier coenzyme Q10.
| |
| | |
| ==== Neural transplantation ====
| |
| The first prospective randomised double-blind sham-placebo controlled trial of dopamine-producing cell transplants failed to show an improvement in quality of life although some significant clinical improvements were seen in patients below the age of 60.<ref> {{cite journal |author=Freed CR, Greene PE, Breeze RE, ''et al'' |title=Transplantation of embryonic dopamine neurons for severe Parkinson's disease |journal=N. Engl. J. Med. |volume=344 |issue=10 |pages=710-9 |year=2001 |pmid=11236774 |doi=}}</ref> A significant problem was the excess release of dopamine by the transplanted tissue, leading to [[dystonia]]s.<ref>{{cite journal |author=Redmond DE |title=Cellular replacement therapy for Parkinson's disease--where we are today? |journal=The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry |volume=8 |issue=5 |pages=457-88 |year=2002 |pmid=12374430 |doi=}}</ref> Research in African green monkeys suggests that the use of [[stem cell]]s might in future provide a similar benefit without inducing dystonias.<ref>{{cite journal |author=Redmond E et al |title=Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells |journal=Procedings of the National Academy of Sciences |volume=104 |issue=29 |year=2007}}</ref>
| |
| | |
| ==== Nutrients ====
| |
| Nutrients have been used in clinical studies and are widely used by people with Parkinson's disease in order to partially treat PD or slow down its deterioration. The L-dopa precursor L-tyrosine was shown to relieve an average of 70% of symptoms.<ref>{{cite journal | author=Lemoine P, Robelin N, Sebert P, Mouret J | title=La L-tyrosine : traitement au long cours de la maladie de Parkinson [L-tyrosine : A long term treatment of Parkinson's Disease] | journal=Comptes rendus academie des sciences | year=1986 | volume=309 | issue= | pages=43-47 | language=French }}</ref> Ferrous iron, the essential cofactor for L-dopa biosynthesis was shown to relieve between 10% and 60% of symptoms in 110 out of 110 patients.<ref>{{cite journal |author=Birkmayer W, Birkmayer JG |title=Iron, a new aid in the treatment of Parkinson patients |journal=J. Neural Transm. |volume=67 |issue=3-4 |pages=287-92 |year=1986 |pmid=3806082 | url=http://www.springerlink.com/link.asp?id=tp15r2g8u6327731}}</ref>
| |
| <ref>{{cite book | editor= Editors Przuntek H , Riederer P | title=Early diagnosis and preventive therapy in Parkinson's disease | date=1989 | publisher= Springer | isbn = 0-387-82080-9 | pages=p. 323}}</ref>
| |
| | |
| More limited efficacy has been obtained with the use of THFA, NADH, and pyridoxine—coenzymes and coenzyme precursors involved in dopamine biosynthesis.<ref>{{cite web | url = http://home.uchicago.edu/~syin/Kang.doc | title = Dopamine biosynthesis | accessdate = 2006-11-04 | format = Word doc | publisher = University of Chicago Personal Web Pages}}</ref> Vitamin C and vitamin E in large doses are commonly used by patients in order to theoretically lessen the cell damage that occurs in Parkinson's disease. This is because the enzymes superoxide dismutase and catalase require these vitamins in order to nullify the superoxide anion, a toxin commonly produced in damaged cells. However, in the randomized controlled trial, DATATOP of patients with early PD, no beneficial effect for vitamin E compared to placebo was seen.<ref name=PSG_1993 />
| |
| | |
| Coenzyme Q10 has more recently been used for similar reasons. MitoQ is a newly developed synthetic substance that is similar in structure and function to coenzyme Q10.
| |
| | |
| ====Qigong====
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| There have been two studies looking at [[qigong]] in Parkinson's disease. In a trial in Bonn, an open-label randomised pilot study in 56 patients found an improvement in motor and non-motor symptoms amongst patients who had undergone one hour of structured Qigong exercise per week in two 8-week blocks. The authors speculate that visualizing the flow of "energy" might act as an internal cue and so help improve movement.<ref>{{cite journal | author = Schmitz-Hubsch T | title = Qigong exercise for the symptoms of Parkinson's disease: a randomized, controlled pilot study. | journal = Mov Disord | volume = 21 | issue = 4 | pages = 543-548 | year = 2006 | pmid = 16229022}}</ref>
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| The second study, however, found Qigong to be ineffective in treating Parkinson's disease. In that study, researchers used a randomized cross-over trial to compare aerobic training with Qigong in advanced Parkinson's disease. Two groups of PD patients were assessed, had 20 sessions of either aerobic exercise or qigong, were assessed again, then after a 2 month gap were switched over for another 20 sessions, and finally assessed again. The authors found an improvement in motor ability and cardiorespiratory function following aerobic exercise, but found no benefit following Qigong. The authors also point out that aerobic exercise had no benefit for patients' quality of life.<ref>{{cite journal |author=Burini D, Farabollini B, Iacucci S, ''et al'' |title=A randomised controlled cross-over trial of aerobic training versus Qigong in advanced Parkinson's disease |journal=Europa medicophysica |volume=42 |issue=3 |pages=231-8 |year=2006 |pmid=17039221 |doi=}}</ref>
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| ====Botox====
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| Recently, [[Botox]] injections are being investigated as a non-FDA approved possible experimental treatment.<ref>{{Citeref patent | US | 6306403 }}</ref>
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| ==Prognosis==
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| PD is not considered to be a fatal disease by itself, but it progresses with time. The average life expectancy of a PD patient is generally lower than for people who do not have the disease.<ref>
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| {{cite web
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| | last =
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| | first =
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| | title = Parkinson's Disease
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| | publisher = Mayo Clinic: College of Medicine
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| | url = http://cancercenter.mayo.edu/mayo/research/parkinsons/
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| | accessdate = 2006-11-04 }}
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| </ref> In the late stages of the disease, PD may cause complications such as choking, pneumonia, and falls that can lead to death.
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| The progression of symptoms in PD may take 20 years or more. In some people, however, the disease progresses more quickly. There is no way to predict what course the disease will take for an individual person. With appropriate treatment, most people with PD can live productive lives for many years after diagnosis.
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| In at least some [http://cat.inist.fr/?aModele=afficheN&cpsidt=3502428 studies], it has been observed that mortality was significantly increased, and longevity decreased among nursing home patients as compared to community dwelling patients.
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| One commonly used system for describing how the symptoms of PD progress is called the [[Hoehn and Yahr scale]]. Another commonly used scale is the [[Unified Parkinson's Disease Rating Scale]] (UPDRS). This much more complicated scale has multiple ratings that measure motor function, and also mental functioning, behavior, mood, and activities of daily living; and motor function. Both the Hoehn and Yahr scale and the UPDRS are used to measure how individuals are faring and how much treatments are helping them. It should be noted that neither scale is specific to Parkinson's disease; that patients with other illnesses can score in the Parkinson's range.
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| ==Notable Parkinson's sufferers==
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| {{further|[[:Category:People with Parkinson's disease|People with Parkinson's disease]]}}
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| One famous sufferer of young-onset Parkinson's is Michael J. Fox, whose book, Lucky Man (2000), focused on his experiences with the disease and his career and family travails in the midst of it. Fox established The Michael J. Fox Foundation for Parkinson's Research to develop a cure for Parkinson's disease within this decade.
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| Other famous sufferers include Pope John Paul II, playwright Eugene O'Neill, artist Salvador Dalí, evangelist Billy Graham, former US Attorney General Janet Reno, and boxer Muhammad Ali. Political figures suffering from it have included Adolf Hitler, Francisco Franco, Deng Xiaoping and Mao Zedong, and former Prime Minister of Canada Pierre Trudeau. Numerous actors have also been afflicted with Parkinson's such as: Terry-Thomas, Deborah Kerr, Kenneth More, Vincent Price, Jim Backus and Michael Redgrave. Helen Beardsley (of Yours, Mine and Ours fame) also suffered from this disease toward the end of her life. Director George Roy Hill (The Sting, Butch Cassidy and the Sundance Kid) also suffered from Parkinson's disease.
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| The film Awakenings (starring Robin Williams and Robert De Niro and based on genuine cases reported by Oliver Sacks) deals sensitively and largely accurately with a similar disease, postencephalitic parkinsonism
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| ==References==
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| <!--See http://en.wikipedia.org/wiki/Wikipedia:Footnotes for an explanation of how to generate footnotes or references using the <ref(erences/)> tags-->
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| * This article contains text released into the public domain from:<br>{{cite web | author=[[National Institute of Neurological Disorders and Stroke]] | title=Parkinson's Disease: Hope Through Research | url=http://www.ninds.nih.gov/disorders/parkinsons_disease/detail_parkinsons_disease.htm | date=January 2006 | publisher=[[National Institutes of Health]]}}
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| <references/></div>
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| {{Mental and behavioural disorders}} | | {{Mental and behavioural disorders}} |
