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Parkinson's disease
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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 skills and speech.
Parkinson's disease belongs to a group of conditions called movement disorders. 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 neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.
PD is the most common cause of chronic progressive parkinsonism, a term which refers to the syndrome of tremor, rigidity, bradykinesia and postural instability. PD is also called "primary parkinsonism" or "idiopathic PD" (classically meaning having no known cause although this term is not strictly true in light of the plethora of newly discovered genetic mutations). While many forms of parkinsonism are "idiopathic", "secondary" cases may result from toxicity most notably drugs, head trauma, or other medical disorders.
Contents
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1 Signs and symptoms

2 Diagnosis

3 Classification

4 Pathology

5 Causes

5.1 Genetic

5.2 Toxins

11 External links

Signs and symptoms
Parkinson disease affects movement (motor symptoms). Typical other symptoms include disorders of mood, behavior, thinking, and sensation (non-motor symptoms). Patients' individual symptoms may be quite dissimilar and progression of the disease is also distinctly individual.
Diagnosis

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.[9] 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.
Clinical practice guidelines introduced in the UK in 2006 state that the diagnosis and follow-up of Parkinson's disease should be done by a specialist in the disease, usually a neurologist with an interest in movement disorders.[10]
Classification
"Parkinson's disease" is the synonym of "primary parkinsonism", i.e. isolated parkinsonism due to a neurodegenerative process without any secondary systemic cause. To say the cause is "unknown" is inaccurate as a clear aetiology exists for some inherited cases of PD such as those caused by the PARKIN mutation. It is possible for a patient to be initially diagnosed with Parkinson's disease but then to develop additional features, requiring revision of the diagnosis.[10]
There are other disorders that are called Parkinson-plus diseases. These include: multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Some include dementia with Lewy bodies (DLB) — while 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 little understood.
These Parkinson-plus diseases may progress more quickly than typical idiopathic Parkinson disease. If cognitive dysfunction occurs before or very early in the course of the movement disorder then DLBD may be suspected. Early postural instability with minimal tremor especially in the context of ophthalmoparesis should suggest PSP. Early autonomic dysfunction including erectile dysfunction and syncope may suggest MSA. The presence of extreme asymmetry with patchy cortical cognitive defects such dysphasia and apraxias especially with 'alien limb' phenomena should suggest CBD.
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.
Wilson's disease (hereditary copper accumulation) may present with parkinsonistic features; young patients presenting with parkinsonism or any other movement disorder must be screened for this rare yet eminently treatable condition by checking liver function, the iris for copper deposits and serum ceruloplasmin levels. Essential tremor may be mistaken for Parkinson's disease but lacks all other features besides tremor.

Pathology

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.
The symptoms of Parkinson's disease result from the loss of pigmented dopamine-secreting (dopaminergic) cells, secreted by the same cells, in the 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.
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.
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.
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 caot 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.[11]
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.[12] 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.[13]
Iron induces aggregation of synuclein by oxidative mechanisms.[14] 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 transgenic mouse model of Parkinson's has been generated by introduction of human wild-type alpha-synuclein into the mouse genome under control of the platelet-derived-growth factor-β promoter.[15]
Causes
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, cerebral anoxia, and drug-induced Parkinson's disease.
Genetic
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. Someone 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.
Genetic forms that have been identified include (external links in this section are to Online Mendelian Inheritance in Man):
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 toxins along with exposure to those toxins.[23] 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 begiings of the Industrial Revolution, and not long thereafter become a common observation in clinical practice. The toxins most strongly suspected at present are certain pesticides and transition-series metals such as manganese or iron, especially those that generate reactive oxygen species,[13][24] and or bind to neuromelanin, as originally suggested by G.C. Cotzias.[25][26] 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.[27]

References

This article contains text released into the public domain from:National Institute of Neurological Disorders and Stroke (January 2006). Parkinson's Disease: Hope Through Research. National Institutes of Health.

^ Lepoutre A, Devos D, Blanchard-Dauphin A, et al (2006). "A specific clinical pattern of camptocormia in Parkinson's disease". J. Neurol. Neurosurg. Psychiatr. 77 (11): 1229-34. PMID 16735399.

^ Fox, Michael (2003). Lucky Man: A Memoir. Hyperion, 214. ISBN 0786888741.

^ Pell M (1996). "On the receptive prosodic loss in Parkinson's disease". Cortex 32 (4): 693-704. PMID 8954247.

^ Deuschl G, Goddemeier C (1998). "Spontaneous and reflex activity of facial muscles in dystonia, Parkinson's disease, and in normal subjects". J. Neurol. Neurosurg. Psychiatr. 64 (3): 320-4. PMID 9527141.

^ Lieberman A (2006). "Depression in Parkinson's disease — a review". Acta Neurol Scand 113 (1): 1-8. PMID 16367891.

^ Ishihara L, Brayne C (2006). "A systematic review of depression and mental illness preceding Parkinson's disease". Acta Neurol Scand 113 (4): 211-20. PMID 16542159.

^ Frank MJ (2005). "Dynamic dopamine modulation in the basal ganglia: a neurocomputational account of cognitive deficits in medicated and nonmedicated Parkinsonism". Journal of cognitive neuroscience 17 (1): 51-72. doi:10.1162/0898929052880093. PMID 15701239.

^ Gupta A, Bluhm R (2004). "Seborrheic dermatitis". Journal of the European Academy of Dermatology and Venereology : JEADV 18 (1): 13-26; quiz 19-20. PMID 14678527.

^ Gelb D, Oliver E, Gilman S (1999). "Diagnostic criteria for Parkinson disease". Arch Neurol 56 (1): 33-9. PMID 9923759.

^ a b c National Institute for Health and Clinical Excellence. Clinical guideline 35: Parkinson's disease. London, June 2006

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