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Parkinson’s disease

 

Parkinson’s disease
Classification and external resources
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
GeneReviews	Parkinson Disease Overview

Parkinson’s disease (also known as Parkinson disease, Parkinson’s, idiopathic parkinsonism, primary parkinsonism, PD, or paralysis agitans) is a degenerative disorder of the central nervous system. It results from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of cell-death is unknown. Early in the course of the disease, the most obvious symptoms are movement-related, including shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, cognitive and behavioural problems may arise, with dementia commonly occurring in the advanced stages of the disease. Other symptoms include sensory, sleep and emotional problems. PD is more common in the elderly 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. 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 dopamine neurons continue to be lost, a point eventually arrives at which these drugs 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 a search of new animal models of the disease and investigations 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 James Parkinson, who published the first detailed description in An Essay on the Shaking Palsy in 1817. Several major organizations promote research and improvement of quality of life of those with the disease and their families. Public awareness campaigns include Parkinson’s disease day on the birthday of James Parkinson, April 11, and the use of a red tulip as the symbol of the disease. People with parkinsonism who have enhanced the public’s awareness include Michael J. Fox and Muhammad Ali.

Contents 1 Classification 2 Signs and symptoms 2.1 Motor 2.2 Neuropsychiatric 2.3 Other 3 Causes 4 Pathology 4.1 Anatomical pathology 4.2 Pathophysiology 4.3 Brain cell death 5 Diagnosis 6 Management 6.1 Levodopa 6.2 Dopamine agonists 6.3 MAO-B inhibitors 6.4 Other drugs 6.5 Surgery and deep brain stimulation 6.6 Rehabilitation 6.7 Diet 6.8 Palliative care 6.9 Other treatments 7 Prognosis 8 Epidemiology 8.1 Risk factors 8.2 Protective factors 9 History 10 Research directions 10.1 Animal models 10.2 Gene therapy 10.3 Neuroprotective treatments 10.4 Neural transplantation 11 Society and culture 11.1 Cost 11.2 Advocacy 11.3 Notable cases 12 References 13 External links

 Classification

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: primary or idiopathic, secondary or acquired, hereditary parkinsonism, and parkinson plus syndromes or multiple system degeneration.^[1] Parkinson’s disease is the most common form of parkinsonism and is usually defined as “primary” parkinsonism, meaning parkinsonism with no external identifiable cause.^[2][3] In recent years several genes that are directly related to some cases of Parkinson’s disease have been discovered. As much as this can go against 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.^[4]

PD is usually classified as a movement disorder, although it also gives rise to several non-motor types of symptoms such as sensory deficits,^[5] cognitive difficulties or sleep problems. Parkinson plus diseases are primary parkinsonisms which present additional features.^[2] They include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy bodies.^[2]

In terms of pathophysiology, PD is considered a synucleinopathy 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.^[6] 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.^[6]

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.^[7] They may represent parts of a continuum or they may be separate diseases.^[7]

Signs and symptoms

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 (…).”

Main article: Signs and symptoms of Parkinson’s disease

Parkinson’s disease affects movement, producing motor symptoms.^[1] Non-motor symptoms, which include autonomic dysfunction, neuropsychiatric problems (mood, cognition, behavior or thought alterations), and sensory and sleep difficulties, are also common.^[1]

Motor

A man with Parkinson’s disease displaying a flexed walking posture pictured in 1892. Photo appeared in Nouvelle Iconographie de la Salpètrière, vol. 5.

Further information: Parkinsonian gait

Four motor symptoms are considered cardinal in PD: tremor, rigidity, slowness of movement, and postural instability.^[1]

Tremor is the most apparent and well-known symptom.^[1] 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.^[1] It is usually a rest tremor: maximal when the limb is at rest and disappearing with voluntary movement and sleep.^[1] 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.^[1] Frequency of PD tremor is between 4 and 6 hertz (cycles per second). A feature of tremor is “pill-rolling”, a term used to describe the tendency of the index finger of the hand to get into contact with the thumb and perform together a circular movement.^[1][8] The term derives from the similarity between the movement in PD patients and the earlier pharmaceutical technique of manually making pills.^[8]

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.^[1] Performance of sequential and simultaneous movement is hindered.^[1] Bradykinesia is the most disabling symptom in the early stages of the disease.^[2] Initial manifestations are problems when performing daily tasks which require fine motor control such as writing, sewing or getting dressed.^[1] Clinical evaluation is based in similar tasks such as alternating movements between both hands or both feet.^[2] 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 patients are barely able to walk yet can still ride a bicycle.^[1] Generally patients have less difficulty when some sort of external cue is provided.^[1][9]

Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, an excessive and continuous contraction of muscles.^[1] In parkinsonism the rigidity can be uniform (lead-pipe rigidity) or ratchety (cogwheel rigidity).^{[1][2][10][11]} The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity.^[12] Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease.^[1] 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.^[13] 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, and secondarily to bone fractures.^[1] Instability is often absent in the initial stages, especially in younger people.^[2] Up to 40% of the patients may experience falls and around 10% may have falls weekly, with number of falls being related to the severity of PD.^[1]

Other recognized motor signs and symptoms include gait and posture disturbances such as festination (rapid shuffling steps and a forward-flexed posture when walking),^[1] speech and swallowing disturbances including voice disorders,^[14] mask-like face expression or small handwriting, although the range of possible motor problems that can appear is large.^[1]

Neuropsychiatric

Parkinson’s disease can cause neuropsychiatric disturbances which can range from mild to severe. This includes disorders of speech, cognition, mood, behaviour, and thought.^[1]

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.^[1][15] 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.^[15]

A person with PD has two to six times the risk of suffering dementia compared to the general population.^[1][15] The prevalence of dementia increases with duration of the disease.^[15] 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.^[15]

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.^[1] 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.^[1][16] Psychotic symptoms—hallucinations or delusions—occur in 4% of patients, 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.^[17][18]

Other

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.^[1] Symptoms can manifest in daytime drowsiness, disturbances in REM sleep, or insomnia.^[1] 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.^[1] Constipation and gastric dysmotility can be severe enough to cause discomfort and even endanger health.^[19] 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.^[1][20] Changes in perception may include an impaired sense of smell, sensation of pain and paresthesia (skin tingling and numbness).^[1] All of these symptoms can occur years before diagnosis of the disease.^[1]

Causes

PDB rendering of Parkin (ligase)

Most people with Parkinson’s disease have idiopathic Parkinson’s disease (having no specific known cause). A small proportion of cases, however, can be attributed to known genetic factors. Other factors have been associated with the risk of developing PD, but no causal relationship has been proven.

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.^[2] 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.^[21]

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.^[4][21] 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.^[4] 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.^[21] Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results.^[22]

The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of Lewy bodies.^[21] 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.^[21] Missense mutations are rare.^[21] On the other hand, multiplications of the SNCA locus account for around 2% of familial cases.^[21] Multiplications have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age-dependent.^[21]

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.^[4] 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.^[4][21] There are many different mutations described in LRRK2, however unequivocal proof of causation only exists for a small number.^[21]

Pathology

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.

Anatomical pathology

The basal ganglia, a group of “brain structures” innervated by the dopaminergic system, are the most seriously affected brain areas in PD.^[23] 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.^[4]

Macroscopic alterations can be noticed on cut surfaces of the brainstem, where neuronal loss can be inferred from a reduction of melanin pigmentation in the substantia nigra and locus coeruleus.^[24] 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.^[24]

 Pathophysiology

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^[25]

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.^[23]

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.^[23] 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.^[23] Scientifically, the motor circuit has been examined the most intensively.^[23]

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.^[23] 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.^[23] 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.^[23]

 Brain cell death

There is speculation of several mechanisms by which the brain cells could be lost.^[26] 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.^[4][27] 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.^[4] 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.^[26][27] In patients 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.^[24]

Other cell-death mechanisms include proteosomal and lysosomal system dysfunction and reduced mitochondrial activity.^[26] 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.^[28]

 Diagnosis

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.

A physician will diagnose Parkinson’s disease from the medical history and a neurological examination.^[1] 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. Patients 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 patient suffered from 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.^[1][29]

Other causes that can secondarily produce a parkinsonian syndrome are Alzheimer’s disease, multiple cerebral infarction and drug-induced parkinsonism.^[29] Parkinson plus syndromes such as progressive supranuclear palsy and multiple system atrophy must be ruled out.^[1] Anti-Parkinson’s medications are typically less effective at controlling symptoms in Parkinson plus syndromes.^[1] 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.^[30] 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.^[2]

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 US National Institute of Neurological Disorders and Stroke.^[1] 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.^[1] Accuracy of diagnostic criteria evaluated at autopsy is 75–90%, with specialists such as neurologists having the highest rates.^[1]

Computed tomography (CT) and magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal.^[31] 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.^[31] 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.^[31] 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 fludeoxyglucose (¹⁸F) for PET.^[31] A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing PD.^[31]

 Management

 

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.^[32] 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.^[32] Treatment in the initial stage aims for an optimal tradeoff between good symptom control and side-effects resulting from enhancement 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.^[32] 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.^[32] When medications are not enough to control symptoms, surgery and deep brain stimulation can be of use.^[33] In the final stages of the disease, palliative care is provided to enhance quality of life.^[34]

 Levodopa

Levodopa has been the most widely used treatment for over 30 years.^[32] L-DOPA is converted into dopamine in the dopaminergic neurons by dopa decarboxylase.^[32] Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor symptoms.^[32]

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.^[32] Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors,^[32] 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.^[32] 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.^[16] 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.^[32][35]

Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of levodopa.^[32] It has been used to complement levodopa; however, its usefulness is limited by possible side effects such as liver damage.^[32] A similarly effective drug, entacapone, has not been shown to cause significant alterations of liver function.^[32] Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.^[32]

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.^[32] 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).^[32] For this reason, levodopa doses are kept as low as possible while maintaining functionality.^[32] Delaying the initiation of therapy with levodopa by using alternatives (dopamine agonists and MAO-B inhibitors) is common practice.^[32] 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.^[32] Most people with PD will eventually need levodopa and later develop motor side effects.^[32]

 Dopamine agonists

Several dopamine agonists that bind to dopaminergic post-synaptic receptors in the brain have similar effects to levodopa.^[32] 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.^[32][36] When used in late PD they are useful at reducing the off periods.^[32] Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride.

Dopamine agonists produce significant, although usually mild, side effects including drowsiness, hallucinations, insomnia, nausea and constipation.^[32] Sometimes side effects appear even at a minimal clinically effective dose, leading the physician to search for a different drug.^[32] Compared with levodopa, dopamine agonists may delay motor complications of medication use but are less effective at controlling symptoms.^[32] Nevertheless, they are usually effective enough to manage symptoms in the initial years.^[2] They tend to be more expensive than levodopa.^[2] 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.^[2] Thus dopamine agonists are the preferred initial treatment for earlier onset, as opposed to levodopa in later onset.^[2] Agonists have been related to a impulse control disorders (such as compulsive sexual activity and eating, and pathological gambling and shopping) even more strongly than levodopa.^[16]

Apomorphine, a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD.^[32] It is administered by intermittent injections or continuous subcutaneous infusions.^[32] Since secondary effects such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be closely monitored.^[32] Two dopamine agonists that are administered through skin patches (lisuride and rotigotine) have been recently found to be useful for patients in initial stages and preliminary positive results has been published on the control of off states in patients in the advanced state.^[35]

 MAO-B inhibitors

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.^[32] 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.^[32] An initial study indicated that selegiline in combination with levodopa increased the risk of death, but this was later disproven.^[32]

 Other drugs

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.^[32] 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.^[37] Examples are the use of clozapine for psychosis, cholinesterase inhibitors for dementia, and modafinil for daytime sleepiness.^[37][38] A 2010 meta-analysis found that non-steroidal anti-inflammatory drugs (apart from acetaminophen 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.^[39]

Surgery and deep brain stimulation

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

Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa, the number of operations declined.^[40] 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.^[40] 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.^[40] Deep brain stimulation (DBS) is the most commonly used surgical treatment. 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 who suffer from 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.^[33] Other, less common, surgical therapies involve the formation of lesions in specific subcortical areas (a technique known as pallidotomy in the case of the lesion being produced in the globus pallidus).^[40]

 Rehabilitation

There is some evidence that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality.^[41][42] Regular physical exercise with or without physiotherapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.^[42] 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.^[43] In terms of improving flexibility and range of motion for patients 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.^[44] 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).^[45] Strengthening exercises have shown improvements in strength and motor function for patients 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 patients should perform exercises 45 minutes to one hour after medications, when the patient is at their best.^[46] 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.^[47] Exercise may improve constipation.^[19]

One of the most widely practiced treatments for speech disorders associated with Parkinson’s disease is the Lee Silverman voice treatment (LSVT).^[41][48] Speech therapy and specifically LSVT may improve speech.^[41] 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.^[41] 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.^[41][49]

 Diet

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).^[19] 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.^[19] 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.^[19]

Levodopa and proteins use the same transportation system in the intestine and the blood-brain barrier, thereby competing for access.^[19] When they are taken together, this results in a reduced effectiveness of the drug.^[19] 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.^[19] To minimize interaction with proteins, levodopa should be taken 30 minutes before meals.^[19] At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.^[19]

Palliative care

Palliative care is often required in the final stages of the disease when all other treatment strategies have become ineffective. The aim of palliative care is to maximize the quality of life for the person with the disease and those surrounding him or her. Some central issues of palliative care are: care in the community while adequate care can be given there, reducing or withdrawing drug intake to reduce drug side effects, preventing pressure ulcers by management of pressure areas of inactive patients, and facilitating end-of-life decisions for the patient as well as involved friends and relatives.^[34]

 Other treatments

Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias.^[50] Its usefulness in PD is an open research topic,^[51] although recent studies have shown no effect by rTMS.^[52] Several nutrients have been proposed as possible treatments; however there is no evidence that vitamins or food additives improve symptoms.^[53] 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.^[54][55][56] 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,^[57] their intake is not free of risks. Life-threatening adverse reactions have been described, such as the neuroleptic malignant syndrome.^[58][59]

 Prognosis

 

Global burden of Parkinson’s disease, measured in disability-adjusted life yearsper 100,000 inhabitants in 2004

  no data

  < 5

  5–12.5

  12.5–20

  20–27.5

  27.5–35

  35–42.5

  42.5–50

  50–57.5

  57.5–65

  65–72.5

  72.5–80

  > 80

PD invariably progresses with time. The Hoehn and Yahr scale, which defines five stages of progression, is commonly used to estimate the progress of the disease.

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.^[60] 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.^[60] In people taking levodopa, the progression time of symptoms to a stage of high dependency from caregivers may be over 15 years.^[60] However, it is hard to predict what course the disease will take for a given individual.^[60] Age is the best predictor of disease progression.^[26] 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.^[26]

Since current therapies improve motor symptoms, disability at present is mainly related to non-motor features of the disease.^[26] Nevertheless, the relationship between disease progression and disability is not linear. Disability is initially related to motor symptoms.^[60] 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.^[60] Finally, after ten years most people with the disease have autonomic disturbances, sleep problems, mood alterations and cognitive decline.^[60] All of these symptoms, especially cognitive decline, greatly increase disability.^[26][60]

The life expectancy of people with PD is reduced.^[60] Mortality ratios are around twice those of unaffected people.^[60] 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.^[60] Death from aspiration pneumonia is twice as common in individuals with PD as in the healthy population.^[60]

 Epidemiology

PD is the second most common neurodegenerative disorder after Alzheimer’s disease.^[61] 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.^[61] 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.^[2] PD may be less prevalent in those of African and Asian ancestry, although this finding is disputed.^[61] Some studies have proposed that it is more common in men than women, but others failed to detect any differences between the two sexes.^[61] The incidence of PD is between 8 and 18 per 100,000 person–years.^[61]

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.^[61] The most frequently replicated relationships are an increased risk of PD in those exposed to pesticides, and a reduced risk in smokers.^[61]

 Risk factors

U.S. Army helicopter spraying Agent Orange over Vietnamese agricultural land during the Vietnam war. Agent Orange has been associated with PD.

Injections of the synthetic neurotoxin MPTP produce a range of symptoms similar to those of PD as well as selective damage to the dopaminergic neurons in the substantia nigra. This observation has led to theorizing that exposure to some environmental toxins may increase the risk of having PD.^[61] Exposure to toxins that have been consistently related to the disease can double the risk of PD, and include certain pesticides, such as rotenone or paraquat, and herbicides, such as Agent Orange.^[61][62][63] Indirect measures of exposure, such as living in rural environments, have been found to increase the risk of PD.^[63] Heavy metals exposure has been proposed to be a risk factor, through possible accumulation in the substantia nigra; however, studies on the issue have been inconclusive.^[61]

Protective factors

Smoking has been related to a reduced risk of having PD. Smokers’ risk of having PD may be reduced down to a third when compared to non-smokers.^[61] The basis for this effect is not known, but possibilities include an effect of nicotine as a dopamine stimulant.^[61] Tobacco smoke contains compounds that act as MAO inhibitors that also might contribute to this effect.^[64] Caffeine consumption also protects against PD.^[65] 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.^[61] The results regarding fat and fatty acids have been contradictory, with various studies reporting protective effects, risk-enhancing effects or no effects.^[61] Finally there have been preliminary indications of a possible protective role of estrogens and anti-inflammatory drugs.^[61]

History

 

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

Several early sources, including an Egyptian papyrus, an Ayurvedic medical treatise, the Bible, or Galen‘s writings, describe symptoms resembling those of PD.^[66] After Galen there are no references unambiguously related to PD until the 17th century.^[66] In the 17th and 18th centuries, several authors wrote about elements of the disease, including Sylvius, Gaubius, Hunter and Chomel.^[66][67][68]

In 1817 an English doctor, James Parkinson, published his essay reporting six cases of paralysis agitans.^[69] 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.^[69][70] 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.^[69] Among other advances, he made the distinction between rigidity, weakness and bradykinesia.^[69] He also championed the renaming of the disease in honor of James Parkinson.^[69]

In 1912 Frederic Lewy described microscopic particles in affected brains, later named “Lewy bodies“.^[69] 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.^[69] 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 its role on PD.^[71] In 1997, alpha-synuclein was found to be the main component of Lewy bodies.^[27]

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.^[67][72] Levodopa was first synthesized in 1911 by Casimir Funk, but it received little attention until the mid 20th century.^[71] It entered clinical practice in 1967 and brought about a revolution in the management of PD.^[71][73] By the late 1980s deep brain stimulation emerged as a possible treatment.^[74]

Research directions

 

There is little prospect of dramatic new PD treatments expected in a short time frame.^[75] 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.^[26]

Animal models

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.^[76] Other predominant toxin-based models employ the insecticide rotenone, the herbicide paraquat and the fungicide maneb.^[77] Models based on toxins are most commonly used in primates. Transgenic rodent models that replicate various aspects of PD have been developed.^[78]

 Gene therapy

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.^[26][79] In 2010 there were four clinical trials using gene therapy in PD.^[26] There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown.^[26] One of these reported positive results in 2011.^[80]

Neuroprotective treatments

While several chemical compounds such as GDNF (chemical structure pictured) have been proposed as neuroprotectors in PD, none have proven efficacy.

Investigations on neuroprotection are at the forefront of PD research. Several molecules have been proposed as potential treatments.^[26] However, none of them have been conclusively demonstrated to reduce degeneration.^[26] 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).^[26] Preclinical research also targets alpha-synuclein.^[75]

 Neural transplantation

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.^[26] 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.^[26] An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonias.^[81] 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.^[26][82] Nevertheless, use of fetal stem cells is controversial.^[26] 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.^[26]

Society and culture

Muhammad Ali at the age of 64 in 2006. He has shown signs of parkinsonism since the age of 38.

Cost

The costs of PD to society are high, but difficult to calculate exactly due to methodological difficulties in research and differences between countries.^[83] 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 US is probably around $10,000 and the total burden around 23 billion dollars.^[83] The largest share of direct cost comes from inpatient care and nursing homes, while the share coming from medications is substantially lower.^[83] Indirect costs are high, due to reduced productivity and the burden on caregivers.^[83] In addition to economic costs, PD reduces quality of life of those with the disease and their caregivers.^[83]

 Advocacy

April 11, the birthday of James Parkinson, has been designated as the world’s Parkinson’s disease day.^[69][84] A red tulip was chosen by several international organizations as the symbol of the disease in 2005: it represents the James Parkinson Tulip cultivar, registered in 1981 by a Dutch horticulturalist.^[84] Advocacy organizations on the disease include the National Parkinson Foundation, which has provided more than $155 million in care, research and support services since 1982,^[85] Parkinson’s Disease Foundation, which has provided more than $90 million for research and $37 million for education and advocacy programs since its founding in 1957 by William Black;^[86][87] the American Parkinson Disease Association, founded in 1961;^[88] and the European Parkinson’s Disease Association, founded in 1992.^[89]

Notable cases

Main article: List of people diagnosed with Parkinson’s disease

Among the many famous people with PD, one who has greatly increased the public awareness of the disease is the actor Michael J. Fox. Fox was diagnosed in 1991 when he was 30, but kept his condition secret from the public for seven years.^[90] He has written two autobiographic books in which his fight against the disease plays a major role,^[91] and appeared before the United States Congress without medication to illustrate the effects of the disease.^[91] 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 US, providing 140 million dollars in research funding between 2001 and 2008.^[91] Fox’s work led him to be named one of the 100 people “whose power, talent or moral example is transforming the world” in 2007 by Time magazine,^[90] and he received an honorary doctorate in medicine from Karolinska Institutet for his contributions to research in Parkinson’s disease.^[92] Another foundation that supports Parkinson’s research was established by professional cyclist Davis Phinney.^[93] The Davis Phinney Foundation strives to improve the lives of those living with Parkinson’s disease by providing them with information and tools.^[94] Muhammad Ali has been called the “world’s most famous Parkinson’s patient”.^[95] He was 42 at diagnosis although he already showed signs of Parkinson’s when he was 38.^[96] Nevertheless, whether he has PD or a parkinsonian syndrome caused by boxing is still an open question.

INDONESIA VERSION

Penyakit Parkinson

Penyakit Parkinson
Klasifikasi dan sumber daya eksternal

Ilustrasi penyakit Parkinson oleh William Richard Gowers, yang pertama kali diterbitkan dalam A Manual Penyakit pada Sistem Saraf (1886)
ICD-10 G20, F02.3
ICD-9 332
OMIM 168600 556500
DiseasesDB 9651
MedlinePlus 000755
eMedicine neuro/304 neuro/635 di muda
pmr/99 rehabilitasi
Penyakit Parkinson GeneReviews Ikhtisar

Penyakit Parkinson (juga dikenal sebagai penyakit Parkinson, Parkinson, parkinson idiopatik, parkinson primer, PD, atau agitans kelumpuhan) adalah gangguan degeneratif sistem saraf pusat. Ini hasil dari kematian dopamin-menghasilkan sel-sel di substansia nigra, sebuah wilayah otak tengah, penyebab kematian sel tidak diketahui. Di awal perjalanan penyakit, gejala yang paling jelas adalah gerakan-terkait, termasuk gemetar, kekakuan, lambatnya gerakan dan kesulitan dengan berjalan dan kiprah. Kemudian, kognitif dan masalah perilaku mungkin timbul, dengan demensia sering terjadi pada tahap lanjut dari penyakit. Gejala lain termasuk sensorik, tidur dan masalah emosional. PD adalah lebih umum pada orang tua dengan sebagian besar kasus terjadi setelah usia 50.

Gejala motor utama secara kolektif disebut parkinson, atau “sindrom parkinsonian”. Penyakit Parkinson sering didefinisikan sebagai sindrom parkinsonian yang idiopatik (tidak memiliki diketahui penyebabnya), meskipun beberapa kasus atipikal memiliki asal-usul genetik. Banyak risiko dan faktor pelindung telah diselidiki: bukti yang paling jelas adalah untuk peningkatan risiko PD pada orang terpapar pestisida tertentu dan mengurangi risiko pada perokok tembakau. Patologi penyakit ini ditandai oleh akumulasi protein yang disebut alpha-synuclein menjadi inklusi disebut badan Lewy di neuron, dan dari pembentukan cukup dan aktivitas dopamin diproduksi di neuron tertentu dalam bagian otak tengah. Diagnosis kasus khas adalah terutama didasarkan pada gejala, dengan tes seperti neuroimaging digunakan untuk konfirmasi.

Pengobatan modern efektif mengelola gejala motor awal penyakit, terutama melalui penggunaan levodopa dan dopamin agonis. Sebagai penyakit berlangsung dan neuron dopamin terus hilang, titik akhirnya tiba di mana obat ini menjadi tidak efektif untuk mengobati gejala dan pada saat yang sama menghasilkan komplikasi yang disebut tardive, ditandai oleh gerakan menggeliat disengaja. Diet dan beberapa bentuk rehabilitasi telah menunjukkan efektivitas beberapa di mengurangi gejala. Bedah dan stimulasi otak dalam telah digunakan untuk mengurangi gejala motor sebagai pilihan terakhir pada kasus yang berat di mana obat tidak efektif. Arah penelitian memasukan sebuah pencarian dari model hewan baru dari penyakit dan penyelidikan dari kegunaan potensi terapi gen, transplantasi stem sel dan agen saraf. Obat untuk mengobati non-gerakan-gejala terkait dari PD, seperti gangguan tidur dan masalah emosional, juga ada.

Penyakit ini dinamai setelah doctor dari Inggris James Parkinson, yang menerbitkan deskripsi rinci pertama di Sebuah Esai tentang Cerebral Gemetar pada tahun 1817. Beberapa organisasi besar mempromosikan penelitian dan peningkatan kualitas hidup dari orang-orang dengan penyakit dan keluarga mereka. Kampanye kesadaran publik termasuk hari penyakit Parkinson pada ulang tahun James Parkinson, 11 April, dan penggunaan tulip merah sebagai simbol dari penyakit. Orang dengan parkinson yang telah meningkatkan kesadaran masyarakat termasuk Michael J. Fox dan Muhammad Ali.

Isi
1 Klasifikasi
2 Tanda dan gejala
2.1 motor
Neuropsikiatrik 2.2
Lainnya 2,3
3 Penyebab
4 Patologi
4.1 Anatomi Patologi
4.2 Patofisiologi
4.3 Otak kematian sel
5 Diagnosis
6 Manajemen
6.1 Levodopa
6.2 Dopamin agonis
6.3 MAO-B inhibitor
6.4 Obat lain
6,5 Bedah dan stimulasi otak dalam
6.6 Rehabilitasi
6,7 Diet
6.8 Perawatan paliatif
6.9 Lain perawatan
7 Prognosis
8 Epidemiologi
8.1 Faktor risiko
8.2 Perlindungan faktor
9 Sejarah
10 Penelitian arah
10.1 Hewan Model
10.2 Terapi gen
10,3 neuroprotektif perawatan
10,4 Neural transplantasi
11 Masyarakat dan budaya
11.1 Biaya
11.2 Advokasi
11.3 Terkemuka kasus
12 Referensi
13 Pranala luar
 

Klasifikasi
Para parkinsonisme Istilah digunakan untuk sindrom bermotor yang utama gejala tremor saat istirahat, kekakuan, memperlambat gerak dan instabilitas postural. Sindrom parkinsonian dapat dibagi menjadi empat subtipe menurut asal mereka: primer atau idiopatik, sekunder atau diperoleh, parkinson turun-temurun, dan ditambah parkinson sindrom atau degenerasi sistem multi [1] penyakit Parkinson adalah bentuk paling umum dari parkinson dan biasanya didefinisikan sebagai. “primer” parkinson, parkinsonism berarti tanpa penyebab yang dapat diidentifikasikan eksternal [2] [3]. Dalam beberapa tahun terakhir beberapa gen yang secara langsung berkaitan dengan beberapa kasus penyakit Parkinson telah ditemukan. Sebanyak ini bisa menentang definisi penyakit Parkinson sebagai penyakit idiopatik, gangguan parkinson genetik dengan perjalanan klinis yang sama dengan PD umumnya termasuk dalam label penyakit Parkinson. Istilah “penyakit Parkinson kekeluargaan” dan “penyakit Parkinson sporadis yang” dapat digunakan untuk membedakan genetik dari bentuk yang benar-benar idiopatik penyakit. [4]

PD biasanya diklasifikasikan sebagai gangguan gerakan, meskipun juga menimbulkan beberapa non-motor jenis gejala seperti defisit sensorik, [5] kognitif kesulitan atau masalah tidur. Ditambah penyakit Parkinson parkinsonisms primer yang hadir fitur tambahan. [2] Mereka termasuk atrofi sistem multi, palsy supranuclear progresif, degenerasi corticobasal dan demensia dengan badan Lewy. [2]

Dalam hal patofisiologi, PD dianggap sebagai synucleinopathy karena adanya akumulasi abnormal dari alfa-synuclein protein dalam otak dalam bentuk badan Lewy, sebagai lawan dari penyakit lain seperti penyakit Alzheimer mana otak terakumulasi protein tau dalam bentuk neurofibrillary kusut [6]. Namun demikian, ada tumpang tindih klinis dan patologis antara tauopathies dan synucleinopathies. Gejala yang paling khas, demensia penyakit Alzheimer, terjadi pada tahap lanjut dari PD, sementara itu adalah umum untuk menemukan kusut neurofibrillary di otak terpengaruh oleh PD. [6]

Demensia dengan badan Lewy (DLB) synucleinopathy lain yang memiliki kesamaan dengan PD, dan terutama dengan subset kasus PD dengan demensia. Namun hubungan antara PD dan DLB adalah kompleks dan masih harus diklarifikasi. [7] Mereka mungkin merupakan bagian dari kontinum atau mereka mungkin penyakit yang terpisah. [7]

Tanda dan gejala

Tulisan tangan seseorang yang dipengaruhi oleh PD dalam Ceramah pada penyakit pada sistem saraf oleh Charcot (1879). Deskripsi asli dari teks menyatakan “Para stroke membentuk huruf sangat tidak teratur dan berliku-liku, sedangkan penyimpangan dan sinuosities adalah dengan lebar sangat terbatas. (…) Down-stroke semua, dengan pengecualian huruf pertama , dibuat dengan ketegasan komparatif dan, pada kenyataannya, hampir normal – lebih halus up-stroke, sebaliknya, semua gemetar dalam penampilan (…).”
Artikel utama: Tanda dan gejala penyakit Parkinson
Penyakit Parkinson mempengaruhi gerakan, menghasilkan gejala motor [1] Non-motor gejala, yang termasuk disfungsi otonom, masalah neuropsikiatri (suasana hati, kognisi, perilaku atau pikiran perubahan), dan kesulitan sensorik dan tidur, juga umum. [1].

 Bermotor

Seorang pria dengan penyakit Parkinson menampilkan menekuk postur berjalan digambarkan pada tahun 1892. Foto muncul di Nouvelle Iconographie de la Salpetriere, vol. 5.
Informasi lebih lanjut: Parkinsonian kiprah
Empat gejala motor dianggap kardinal di PD:. Tremor, kekakuan, lambatnya gerakan, dan instabilitas postural [1]

Tremor adalah gejala yang paling jelas dan terkenal [1] Ini adalah yang paling umum;. Meskipun sekitar 30% dari individu dengan PD tidak memiliki tremor saat onset penyakit, yang paling berkembang sebagai penyakit berlangsung [1] Hal ini biasanya. getaran istirahat: maksimal saat ekstremitas berada pada istirahat dan menghilang dengan gerakan sukarela dan tidur [1] Ini mempengaruhi untuk sebagian besar bagian paling distal ekstremitas dan saat onset biasanya hanya muncul di lengan tunggal atau kaki, menjadi bilateral. kemudian [1]. Frekuensi getaran PD adalah antara 4 dan 6 hertz (siklus per detik). Sebuah fitur getaran adalah “pil-rolling”, sebuah istilah yang digunakan untuk menggambarkan kecenderungan jari telunjuk dari tangan untuk mendapatkan ke dalam kontak dengan ibu jari dan melakukan bersama-sama gerakan melingkar [1] [8]. Istilah ini berasal dari kesamaan antara gerakan pada pasien PD dan teknik sebelumnya farmasi secara manual membuat pil. [8]

Bradykinesia (lambatnya gerakan) adalah fitur lain karakteristik dari PD, dan berhubungan dengan kesulitan sepanjang perjalanan seluruh proses gerakan, mulai dari perencanaan sampai inisiasi dan akhirnya pelaksanaan gerakan [1] Kinerja gerakan sekuensial dan simultan terhalang.. [1] bradykinesia adalah gejala yang paling melumpuhkan pada tahap awal penyakit ini. [2] manifestasi awal masalah ketika melakukan tugas sehari-hari yang memerlukan kontrol motorik halus seperti menulis, menjahit atau berpakaian [1] evaluasi klinis. yang berbasis di tugas-tugas serupa seperti bergantian gerakan antara kedua tangan atau kedua kaki [2] bradykinesia tidak sama untuk semua gerakan atau kali.. Hal ini dimodifikasi oleh aktivitas atau keadaan emosi subjek, ke titik bahwa beberapa pasien yang hampir tidak bisa berjalan namun masih bisa naik sepeda [1]. Umumnya pasien mengalami sedikit kesulitan ketika beberapa jenis isyarat eksternal disediakan. [1 ] [9]

Kekakuan adalah kekakuan dan ketahanan terhadap gerakan anggota tubuh yang disebabkan oleh nada otot meningkat, kontraksi berlebihan dan terus menerus otot [1] Dalam parkinsonisme kekakuan dapat seragam (timbal-pipa kekakuan) atau ratchety (kekakuan cogwheel).. [1] [2 ] [10] [11] Kombinasi tremor dan peningkatan nada dianggap di asal kekakuan cogwheel [12] Kekakuan mungkin berhubungan dengan nyeri sendi;. sakit seperti menjadi manifestasi awal dari penyakit yang sering [1]. Pada tahap awal penyakit Parkinson, kekakuan seringkali asimetris dan cenderung mempengaruhi otot leher dan bahu sebelum otot-otot wajah dan ekstremitas [13] Dengan perkembangan penyakit, kekakuan biasanya mempengaruhi seluruh tubuh dan mengurangi. kemampuan untuk bergerak.

Instabilitas postural adalah khas dalam tahap akhir dari penyakit, yang menyebabkan gangguan keseimbangan dan jatuh sering, dan sekunder untuk patah tulang [1]. Ketidakstabilan ini sering absen pada tahap awal, terutama pada orang muda. [2] Sampai dengan 40% dari pasien mungkin mengalami jatuh dan sekitar 10% mungkin telah jatuh mingguan, dengan jumlah yang jatuh berhubungan dengan keparahan dari PD [1].

Tanda-tanda motor lain diakui dan gejala termasuk gangguan gaya berjalan dan postur seperti festination (langkah mengocok cepat dan postur tubuh ke depan tertekuk ketika berjalan), [1] berbicara dan gangguan menelan termasuk gangguan suara, [14] seperti topeng ekspresi wajah atau tulisan tangan kecil , meskipun berbagai masalah motorik yang mungkin yang dapat muncul adalah besar [1].

 Neuropsikiatrik
Penyakit Parkinson dapat menyebabkan gangguan neuropsikiatri yang bisa berkisar dari ringan sampai parah. Ini termasuk gangguan berbicara, kognisi, mood, perilaku, dan pikiran [1].

Gangguan kognitif dapat terjadi pada tahap awal penyakit dan kadang-kadang sebelum diagnosis, dan peningkatan prevalensi dengan durasi penyakit [1] [15]. Defisit kognitif yang paling umum pada individu yang terkena adalah disfungsi eksekutif, yang dapat mencakup masalah dengan perencanaan, fleksibilitas kognitif, berpikir abstrak, akuisisi aturan, memulai tindakan yang tepat dan tindakan tidak pantas menghambat, dan memilih informasi sensorik relevan. Fluktuasi perhatian dan memperlambat kecepatan kognitif antara kesulitan kognitif lainnya. Memori dipengaruhi, khususnya dalam mengingat informasi yang dipelajari. Namun demikian, perbaikan muncul ketika mengingat dibantu oleh isyarat. Kesulitan visuospatial juga merupakan bagian dari penyakit, dilihat misalnya ketika individu diminta untuk melakukan tes pengenalan wajah dan persepsi orientasi garis yang ditarik [15].

Seseorang dengan PD memiliki dua sampai enam kali risiko menderita demensia dibandingkan dengan populasi umum [1] [15]. Prevalensi demensia meningkat dengan durasi penyakit. [15] Demensia dikaitkan dengan berkurangnya kualitas hidup di orang dengan PD dan pengasuh mereka, meningkatnya kematian, dan probabilitas yang lebih tinggi membutuhkan perawatan di rumah. [15]

Perubahan perilaku dan suasana hati lebih sering terjadi pada PD tanpa gangguan kognitif dibandingkan pada populasi umum, dan biasanya hadir dalam PD dengan demensia. Kesulitan suasana hati yang paling sering adalah depresi, apatis dan kecemasan. [1] perilaku kontrol impuls seperti obat-obatan dan keinginan berlebihan, makan pesta, hypersexuality, atau judi patologis dapat muncul di PD dan telah terkait dengan obat yang digunakan untuk mengelola penyakit ini. [1] [16] psikotik gejala-halusinasi atau delusi-terjadi pada 4% pasien, dan diasumsikan bahwa tergesa-gesa utama fenomena psikotik pada penyakit Parkinson adalah kelebihan dopaminergik sekunder untuk pengobatan; karena itu menjadi lebih umum dengan bertambahnya usia dan asupan levodopa [17]. [18]

Lain-lain
Selain gejala kognitif dan motor, PD dapat merusak fungsi tubuh lainnya. Masalah tidur adalah fitur dari penyakit dan dapat diperburuk oleh obat [1] Gejala. Dapat terwujud dalam rasa kantuk di siang hari, gangguan dalam tidur REM, atau insomnia. [1] Perubahan dalam sistem saraf otonom dapat menyebabkan hipotensi ortostatik (darah rendah tekanan terhadap berdiri), kulit berminyak dan berkeringat berlebihan, inkontinensia urin dan fungsi seksual diubah [1]. Sembelit dan dismotilitas lambung dapat cukup parah untuk menyebabkan ketidaknyamanan dan bahkan membahayakan kesehatan [19]. PD adalah terkait dengan beberapa mata dan kelainan visi seperti sebagai penurunan tingkat berkedip, mata kering, mata mengejar kekurangan (pelacakan mata) dan gerakan saccadic (gerakan otomatis cepat dari kedua mata di arah yang sama), kesulitan dalam mengarahkan pandangannya ke atas, dan penglihatan kabur atau ganda [1]. [20] Perubahan dalam persepsi mungkin termasuk rasa gangguan penciuman, sensasi rasa sakit dan paresthesia (kesemutan dan mati rasa kulit) [1]. Semua gejala ini dapat terjadi tahun sebelum diagnosis penyakit. [1]

 Penyebab

PDB rendering Parkin (ligase)
Kebanyakan orang dengan penyakit Parkinson memiliki penyakit Parkinson idiopatik (tidak memiliki diketahui penyebabnya yang spesifik). Sebagian kecil kasus, bagaimanapun, dapat dikaitkan dengan faktor genetik dikenal. Faktor lain telah dikaitkan dengan risiko pengembangan PD, tetapi tidak ada hubungan kausal telah terbukti.

PD tradisional telah dianggap sebagai gangguan non-genetik;. Namun, sekitar 15% dari individu dengan PD memiliki kerabat tingkat pertama yang memiliki penyakit [2] Setidaknya 5% dari orang kini diketahui memiliki bentuk penyakit yang terjadi karena mutasi dari salah satu gen yang spesifik. [21]

Mutasi pada gen-gen tertentu telah meyakinkan terbukti menyebabkan PD. Ini kode gen untuk alfa-synuclein (SPMB), Parkin (PRKN), leusin kaya kinase mengulang 2 (LRRK2 atau dardarin), PTEN-diinduksi kinase putatif 1 (PINK1), DJ-1 dan ATP13A2. [4] [21] Dalam kebanyakan kasus, orang dengan mutasi ini akan mengembangkan PD. Dengan pengecualian LRRK2, bagaimanapun, mereka account hanya minoritas kecil dari kasus PD [4] PD-terkait paling ekstensif dipelajari gen SPMB dan LRRK2.. Mutasi pada gen termasuk SPMB, LRRK2 dan glucocerebrosidase (GBA) telah ditemukan menjadi faktor risiko untuk PD sporadis. Mutasi di GBA diketahui menyebabkan penyakit Gaucher. [21] Genome-wide studi hubungan, yang mencari alel bermutasi dengan penetrasi yang rendah dalam kasus-kasus sporadis, kini telah menghasilkan banyak hasil positif. [22]

Peran dari gen SPMB adalah penting dalam PD karena protein alpha-synuclein adalah komponen utama dari badan Lewy. [21] mutasi missense gen (di mana nukleotida tunggal berubah), dan duplikasi dan triplications dari lokus yang berisi itu telah ditemukan dalam kelompok-kelompok yang berbeda dengan PD keluarga [21] missense mutasi jarang terjadi.. [21] Di sisi lain, perkalian dari account lokus SPMB untuk sekitar 2% dari kasus keluarga. [21] perkalian telah ditemukan di asimtomatik operator, yang menunjukkan bahwa penetrasi tidak lengkap atau usia tergantung. [21]

Gen LRRK2 (PARK8) mengkode untuk protein yang disebut dardarin. Nama dardarin diambil dari kata Basque untuk tremor, karena gen ini pertama kali diidentifikasi pada keluarga dari Inggris dan bagian utara Spanyol [4]. Mutasi di LRRK2 adalah penyebab paling umum dikenal PD keluarga dan sporadis, akuntansi untuk sekitar 5 % dari individu dengan riwayat keluarga penyakit dan 3% dari kasus sporadis. [4] [21] Ada banyak mutasi yang berbeda dijelaskan dalam LRRK2, namun bukti tegas dari sebab-akibat hanya ada untuk sejumlah kecil. [21]

 Patologi

Sebuah tubuh Lewy (coklat patri) dalam sel otak substantia nigra dalam penyakit Parkinson. Warna coklat adalah pewarnaan imunohistokimia positif untuk alfa-synuclein.

patologi anatomi
Ganglia basal, sebuah kelompok “struktur otak” diinervasi oleh sistem dopaminergik, adalah yang paling serius terkena dampak area otak di PD [23]. Karakteristik patologis utama dari PD adalah kematian sel dalam substantia nigra dan, lebih khusus, ventral (depan) bagian dari pars compacta, yang mempengaruhi hingga 70% dari kematian sel dengan waktu terjadi. [4]

Perubahan makroskopik dapat melihat pada permukaan dipotong dari batang otak, di mana hilangnya neuron dapat disimpulkan dari pengurangan pigmentasi melanin dalam substantia nigra dan lokus coeruleus [24]. Para histopatologi (anatomi mikroskopik) dari substantia nigra dan beberapa daerah otak lainnya menunjukkan hilangnya neuron dan badan Lewy dalam banyak sel-sel saraf yang tersisa. Hilangnya neuron disertai dengan kematian astrosit (berbentuk bintang sel-sel glial) dan aktivasi dari mikroglia (jenis lain dari sel glial). Badan Lewy adalah fitur kunci dari PD patologis. [24]

Patofisiologi

A. Skema awal perkembangan deposito tubuh Lewy pada tahap pertama penyakit Parkinson, seperti yang diusulkan oleh Braak dan rekan
B. Lokalisasi wilayah volume otak penurunan yang signifikan di PD awal dibandingkan dengan kelompok peserta tanpa penyakit dalam studi neuroimaging, yang menyimpulkan bahwa kerusakan batang otak mungkin tahap pertama diidentifikasi PD neuropatologi [25]
Gejala utama hasil penyakit Parkinson dari kegiatan sangat mengurangi sel mensekresi dopamin yang disebabkan oleh kematian sel di daerah pars compacta dari substantia nigra. [23]

Ada lima jalur utama di otak yang menghubungkan daerah otak lainnya dengan ganglia basal. Ini dikenal sebagai motor, oculo-motor, sirkuit asosiatif, limbik dan orbitofrontal, dengan nama yang menunjukkan area proyeksi utama dari setiap sirkuit [23]. Semua dari mereka yang terkena di PD, dan gangguan mereka menjelaskan banyak gejala penyakit sejak sirkuit ini terlibat dalam berbagai fungsi termasuk gerakan, perhatian dan belajar. [23] Secara ilmiah, sirkuit motor telah diperiksa paling intensif [23].

Sebuah model konseptual tertentu dari sirkuit motor dan perubahan dengan PD telah pengaruh besar sejak tahun 1980, meskipun beberapa keterbatasan telah menunjukkan yang telah menyebabkan modifikasi. [23] Dalam model ini, ganglia basal biasanya memberikan pengaruh penghambatan konstan pada berbagai sistem motor, mencegah mereka dari menjadi aktif pada waktu yang tidak tepat. Ketika keputusan dibuat untuk melakukan suatu tindakan tertentu, penghambatan berkurang untuk sistem motor yang diperlukan, sehingga melepaskannya untuk aktivasi. Dopamin bertindak untuk memfasilitasi pelepasan inhibisi, tingkat begitu tinggi fungsi dopamin cenderung mempromosikan aktivitas motorik, sementara tingkat rendah fungsi dopamin, seperti yang terjadi pada PD, permintaan pengerahan tenaga lebih besar dari upaya untuk setiap gerakan yang diberikan. Jadi efek bersih dari deplesi dopamin adalah untuk menghasilkan hypokinesia, pengurangan secara keseluruhan dalam output bermotor [23]. Obat yang digunakan untuk mengobati PD, sebaliknya, bisa menghasilkan aktivitas dopamin berlebihan, yang memungkinkan sistem motor yang akan diaktifkan pada saat yang tidak tepat dan dengan demikian menghasilkan dyskinesias [23].

 Kematian otak sel
Ada spekulasi beberapa mekanisme dimana sel-sel otak bisa hilang [26]. Salah satu mekanisme terdiri dari akumulasi abnormal dari protein alfa-synuclein terikat ubiquitin dalam sel yang rusak. Protein ini tidak larut terakumulasi di dalam neuron membentuk inklusi disebut Lewy tubuh [4]. [27] Menurut pementasan Braak, klasifikasi penyakit berdasarkan temuan patologis, badan Lewy pertama kali muncul di olfactory bulb, medulla oblongata dan pons tegmentum, dengan individu pada tahap ini menjadi asimtomatik. Sebagai penyakit berlangsung, badan Lewy kemudian berkembang di substantia nigra, area otak tengah dan otak depan basal, dan langkah terakhir neokorteks [4] Situs-situs otak adalah tempat utama degenerasi saraf di PD,. Namun, badan Lewy mungkin tidak menyebabkan kematian sel dan mereka mungkin menjadi pelindung [26]. [27] Pada pasien dengan demensia, kehadiran umum dari badan Lewy yang umum di daerah kortikal. Kusut neurofibrillary dan plak pikun, karakteristik penyakit Alzheimer, yang tidak umum kecuali orang itu gila. [24]

Lain-sel mati Mekanisme ini termasuk disfungsi sistem proteosomal dan lisosomal dan aktivitas mitokondria berkurang [26]. Besi akumulasi dalam substantia nigra biasanya diamati dalam hubungannya dengan inklusi protein. Ini mungkin berhubungan dengan stres oksidatif, agregasi protein dan kematian neuronal, tetapi mekanisme tidak sepenuhnya dipahami [28].

Diagnosis

Fludeoxyglucose (18F) (FDG)] PET scan otak yang sehat. Daerah panas mencerminkan penyerapan glukosa yang lebih tinggi. Sebuah penurunan aktivitas di ganglia basal dapat membantu dalam mendiagnosa penyakit Parkinson.
Seorang dokter akan mendiagnosa penyakit Parkinson dari riwayat medis dan pemeriksaan neurologis [1]. Tidak ada tes laboratorium yang jelas akan mengidentifikasi penyakit, tetapi pemindaian otak kadang-kadang digunakan untuk mengesampingkan gangguan yang dapat menimbulkan gejala yang sama. Pasien dapat diberikan levodopa dan lega yang dihasilkan dari gangguan motorik cenderung untuk mengkonfirmasikan diagnosis. Temuan badan Lewy di otak tengah pada otopsi biasanya dianggap bukti bahwa pasien menderita penyakit Parkinson. Kemajuan dari penyakit dari waktu ke waktu dapat mengungkapkan itu bukan penyakit Parkinson, dan beberapa pihak berwenang merekomendasikan bahwa diagnosis secara periodik terakhir [1] [29].

Penyebab lain yang secara sekunder dapat menghasilkan sindrom parkinsonian adalah penyakit Alzheimer, infark serebral ganda dan obat-induced parkinson. [29] Parkinson ditambah sindrom seperti palsy supranuclear progresif dan atrofi sistem multi harus dikesampingkan [1] obat anti-Parkinson. biasanya kurang efektif mengendalikan gejala di Parkinson ditambah sindrom [1]. angka kemajuan lebih cepat, disfungsi kognitif awal atau instabilitas postural, tremor minimal atau simetri saat onset mungkin mengindikasikan penyakit Parkinson ditambah ketimbang PD itu sendiri. [30] bentuk genetik biasanya diklasifikasikan sebagai PD, meskipun istilah penyakit Parkinson keluarga dan parkinson kekeluargaan yang digunakan untuk entitas penyakit dengan pola dominan atau resesif autosomal dari warisan. [2]

Organisasi medis telah menciptakan kriteria diagnostik untuk kemudahan dan standarisasi proses diagnostik, terutama pada tahap awal penyakit ini. Kriteria yang paling banyak dikenal berasal dari Otak Masyarakat Bank Parkinson Inggris Penyakit dan US National Institute of Neurological Gangguan dan Stroke [1]. Kriteria PD Otak Bank Masyarakat membutuhkan lambatnya gerakan (bradykinesia) plus kekakuan, tremor istirahat, atau postural ketidakstabilan. Kemungkinan penyebab lain untuk gejala ini harus dikesampingkan. Akhirnya, tiga atau lebih dari fitur berikut diperlukan saat onset atau evolusi: onset sepihak, tremor saat istirahat, kemajuan dalam waktu, asimetri gejala motorik, respon terhadap levodopa setidaknya selama lima tahun, perjalanan klinis setidaknya sepuluh tahun dan penampilan dari dyskinesias diinduksi oleh asupan levodopa berlebihan [1] Akurasi kriteria diagnostik dievaluasi pada otopsi adalah 75-90%, dengan spesialis seperti ahli saraf memiliki tingkat tertinggi.. [1]

Computed tomography (CT) dan magnetic resonance imaging scan otak (MRI) dari orang-orang dengan PD biasanya tampak normal. [31] Teknik-teknik ini tetap berguna untuk menyingkirkan penyakit lain yang dapat menyebabkan parkinson sekunder, seperti tumor basal ganglia, vaskular patologi dan hidrosefalus [31]. Sebuah teknik khusus dari MRI, difusi MRI, telah dilaporkan berguna untuk membedakan antara parkinson khas dan atipikal, meskipun nilai yang tepat diagnostik masih dalam penyelidikan. [31] fungsi dopaminergik di ganglia basal dapat diukur dengan PET dan SPECT radiotracers yang berbeda. Contohnya adalah ioflupane (123I) (nama dagang DaTSCAN) dan iometopane (Dopascan) untuk SPECT atau fludeoxyglucose (18F) untuk PET. [31] Sebuah pola aktivitas dopaminergik berkurang di ganglia basal dapat membantu dalam mendiagnosa PD. [31]

 Manajemen
Artikel utama: Pengobatan penyakit Parkinson
Tidak ada obat untuk penyakit Parkinson, tetapi obat-obatan, operasi dan manajemen multidisiplin dapat memberikan bantuan dari gejala. Keluarga utama dari obat yang berguna untuk mengobati gejala motor levodopa (biasanya dikombinasikan dengan inhibitor dekarboksilase dopa atau inhibitor COMT), agonis dopamin dan MAO-B inhibitor [32]. Tahap penyakit menentukan kelompok mana yang paling berguna. Dua tahap biasanya dibedakan:. Tahap awal di mana individu dengan PD telah mengembangkan beberapa cacat yang dia butuhkan pengobatan farmakologis, maka tahap kedua di mana seorang individu mengembangkan komplikasi motorik yang berhubungan dengan penggunaan levodopa [32] Pengobatan di awal tahap bertujuan untuk tradeoff yang optimal antara kontrol gejala yang baik dan efek samping yang dihasilkan dari peningkatan fungsi dopaminergik. Awal levodopa (atau L-dopa) pengobatan mungkin tertunda dengan menggunakan obat lain seperti MAO-B inhibitor dan agonis dopamin, dengan harapan menunda timbulnya dyskinesias [32] Pada tahap kedua. Tujuannya adalah untuk mengurangi gejala sambil mengontrol fluktuasi dari respon terhadap pengobatan. Penarikan mendadak dari obat atau berlebihan harus dikelola [32]. Bila obat tidak cukup untuk mengontrol gejala, operasi dan stimulasi otak dalam dapat berguna. [33] Pada tahap akhir dari penyakit, perawatan paliatif diberikan untuk meningkatkan kualitas hidup [34].

Levodopa
Levodopa telah menjadi pengobatan yang paling banyak digunakan untuk lebih dari 30 tahun [32]. L-dopa diubah menjadi dopamin di neuron dopaminergik oleh dopa dekarboksilase. [32] Karena gejala motor yang diproduksi oleh kurangnya dopamin dalam substansia nigra, yang administrasi L-dopa sementara mengurangi gejala motor. [32]

Hanya 5-10% L-dopa melintasi penghalang darah-otak. Sisanya sering dimetabolisme untuk dopamin di tempat lain, menyebabkan berbagai efek samping termasuk mual, diskinesia dan kekakuan sendi [32]. Carbidopa dan benserazide adalah inhibitor dekarboksilase dopa perifer, [32] yang membantu mencegah metabolisme L-dopa sebelum mencapai neuron dopaminergik, sehingga mengurangi efek samping dan meningkatkan bioavailabilitas. Mereka umumnya diberikan sebagai persiapan kombinasi dengan levodopa [32] persiapan yang ada. Yang carbidopa / levodopa (co-careldopa) dan benserazide / levodopa (co-beneldopa). Levodopa telah terkait dengan sindrom disregulasi dopamin, yang merupakan berlebihan kompulsif obat, dan punding [16]. Ada versi rilis dikendalikan dari levodopa dalam bentuk infus intravena dan usus yang menyebar efek obat. Ini lambat-release persiapan levodopa belum menunjukkan peningkatan kontrol gejala motor atau komplikasi motor ketika dibandingkan dengan persiapan segera dibebaskan. [32] [35]

Tolcapone menghambat enzim COMT, yang menurunkan dopamin, sehingga memperpanjang efek levodopa [32] ini telah digunakan untuk melengkapi levodopa;.. Namun, kegunaannya dibatasi oleh efek samping yang mungkin seperti kerusakan hati [32] Sebuah obat sama efektif , entacapone, belum terbukti menyebabkan perubahan yang signifikan dari fungsi hati [32] persiapan Berlisensi dari entacapone mengandung entacapone sendiri atau dalam kombinasi dengan carbidopa dan levodopa.. [32]

Persiapan levodopa memimpin dalam jangka panjang untuk pengembangan komplikasi motorik ditandai dengan gerakan tak terkendali yang disebut dyskinesias dan fluktuasi dalam respon terhadap pengobatan [32]. Ketika ini terjadi orang dengan PD dapat berubah dari fase dengan respon yang baik terhadap obat dan beberapa gejala ( “pada” negara), untuk fase dengan tidak ada respon terhadap pengobatan dan gejala motor yang signifikan (“off” negara) [32] Untuk alasan ini,. dosis levodopa yang dijaga serendah mungkin dengan tetap menjaga fungsi [32] Menunda inisiasi. terapi dengan levodopa dengan menggunakan alternatif (agonis dopamin dan MAO-B inhibitor) adalah praktek yang umum. [32] Sebuah strategi mantan untuk mengurangi komplikasi motor untuk menarik L-dopa obat untuk beberapa waktu. Ini tidak disarankan sekarang, karena dapat membawa efek samping yang berbahaya seperti sindrom neuroleptik ganas. [32] Kebanyakan orang dengan PD akhirnya akan membutuhkan levodopa dan kemudian mengembangkan efek samping motorik. [32]

 agonis Dopamin
Beberapa agonis dopamin yang mengikat pasca-sinaptik dopaminergik reseptor di otak memiliki efek yang sama terhadap levodopa [32] ini pada awalnya digunakan untuk individu mengalami on-off fluktuasi dan diskinesia sebagai terapi komplementer untuk levodopa,. Mereka sekarang terutama digunakan pada mereka sendiri sebagai terapi awal untuk gejala motor dengan tujuan menunda komplikasi bermotor [32]. [36] Ketika digunakan di PD an mereka berguna untuk mengurangi periode off. [32] agonis Dopamin termasuk bromokriptin, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine dan lisuride.

Agonis dopamin menghasilkan signifikan, meskipun biasanya ringan, efek samping termasuk rasa kantuk, halusinasi, mual insomnia, dan sembelit. [32] Kadang-kadang efek samping muncul bahkan pada dosis klinis efektif minim, menyebabkan dokter untuk mencari obat yang berbeda. [32] Dibandingkan dengan levodopa, agonis dopamin dapat menunda komplikasi motor menggunakan obat tetapi kurang efektif mengendalikan gejala [32] Meskipun demikian, mereka biasanya cukup efektif untuk mengelola gejala pada tahun-tahun awal.. [2] Mereka cenderung lebih mahal daripada levodopa [2]. dyskinesias akibat agonis dopamin jarang pada orang muda yang memiliki PD, namun seiring dengan efek samping lainnya, menjadi lebih umum dengan usia saat onset [2] Jadi. agonis dopamin adalah pengobatan awal yang lebih disukai untuk onset awal, sebagai lawan terhadap levodopa dalam onset kemudian [2]. Agonis telah terkait dengan gangguan impuls kontrol (seperti aktivitas seksual kompulsif dan makan, dan judi patologis dan belanja) bahkan lebih kuat dari levodopa. [16]

Apomorphine, suatu agonis dopamin non-oral, dapat digunakan untuk mengurangi off periode dan tardive di PD-an [32]. Hal ini dikelola oleh suntikan subkutan intermiten atau kontinu infus [32]. Karena efek sekunder seperti kebingungan dan halusinasi yang umum , individu-individu yang menerima pengobatan apomorphine harus diawasi secara ketat. [32] Dua agonis dopamin yang diberikan melalui patch kulit (lisuride dan rotigotine) telah baru-baru ini ditemukan bermanfaat bagi pasien dalam tahap awal dan hasil positif awal telah dipublikasikan pada kontrol mematikan negara pada pasien di negara maju [35].

MAO-B inhibitor
MAO-B inhibitor (selegiline dan rasagiline) meningkatkan tingkat dopamin di ganglia basal dengan menghalangi metabolisme. Mereka menghambat monoamin oksidase-B (MAO-B) yang memecah dopamin disekresikan oleh neuron dopaminergik. Pengurangan MAO-B hasil kegiatan dalam peningkatan L-dopa di striatum [32] Seperti agonis dopamin, MAO-B inhibitor yang digunakan sebagai monoterapi memperbaiki gejala motorik dan menunda kebutuhan untuk levodopa pada penyakit awal, tetapi menghasilkan efek yang lebih merugikan dan. kurang efektif daripada levodopa. Ada beberapa studi efektivitas mereka dalam stadium lanjut, meskipun hasil menunjukkan bahwa mereka berguna untuk mengurangi fluktuasi antara on dan off periode [32]. Sebuah studi awal mengindikasikan bahwa selegiline dalam kombinasi dengan levodopa meningkatkan risiko kematian, tapi ini kemudian disproven. [32]

 Obat lain
Obat lain seperti amantadine dan antikolinergik mungkin berguna sebagai pengobatan gejala motor. Namun, bukti mendukung mereka tidak memiliki kualitas, sehingga mereka tidak pengobatan pilihan pertama. [32] Selain gejala motor, PD disertai dengan beragam gejala. Sejumlah obat telah digunakan untuk mengobati beberapa masalah [37]. Contohnya adalah penggunaan clozapine untuk psikosis, cholinesterase inhibitor untuk demensia, dan modafinil untuk kantuk di siang hari. [37] [38] Sebuah meta-analisis 2010 menemukan bahwa non-steroid anti-inflammatory drugs (selain asetaminofen dan aspirin), telah dihubungkan dengan setidaknya 15 persen (lebih tinggi dalam jangka panjang dan pengguna biasa) pengurangan kejadian perkembangan penyakit Parkinson. [39]

  Epidemiologi
PD adalah gangguan neurodegeneratif kedua yang paling umum setelah penyakit Alzheimer [61]. Prevalensi (proporsi dalam populasi pada suatu waktu tertentu) dari PD adalah sekitar 0,3% dari seluruh penduduk di negara-negara industri. PD lebih umum pada lansia dan prevalensi meningkat dari 1% pada mereka yang 60 tahun lebih dari usia sampai 4% dari populasi lebih dari 80 [61]. Rata-rata usia onset adalah sekitar 60 tahun, meskipun 5-10% dari kasus, diklasifikasikan sebagai onset muda, mulai antara usia 20 dan 50 [2]. PD mungkin kurang lazim dalam orang-orang keturunan Afrika dan Asia, meskipun temuan ini diperdebatkan. [61] Beberapa penelitian telah mengusulkan bahwa itu adalah lebih umum pada laki-laki daripada perempuan, tetapi yang lain gagal untuk mendeteksi perbedaan antara kedua jenis kelamin. [61] Insiden PD adalah antara 8 dan 18 per 100.000 orang-tahun [61].

Banyak faktor risiko dan faktor pelindung telah diusulkan, kadang-kadang dalam kaitannya dengan teori-teori tentang kemungkinan mekanisme penyakit ini, namun belum ada yang meyakinkan terkait dengan PD oleh bukti empiris. Ketika studi epidemiologis telah dilakukan dalam rangka untuk menguji hubungan antara faktor yang diberikan dan PD, mereka sering telah cacat dan hasil mereka dalam beberapa kasus telah bertentangan [61]. Hubungan yang paling sering ditiru adalah peningkatan risiko PD di mereka yang terpapar pestisida, dan mengurangi risiko pada perokok [61].

 Faktor risiko

US Army helikopter penyemprotan Agen Oranye atas tanah pertanian Vietnam selama perang Vietnam. Agen Oranye telah dikaitkan dengan PD.

Suntikan dari MPTP neurotoksin sintetik menghasilkan berbagai gejala mirip dengan PD serta kerusakan selektif ke neuron dopaminergik di substansia nigra. Pengamatan ini telah menyebabkan teori bahwa paparan terhadap beberapa racun lingkungan dapat meningkatkan risiko memiliki PD. [61] Paparan racun yang telah secara konsisten terkait dengan penyakit ini dapat melipatgandakan risiko PD, dan termasuk pestisida tertentu, seperti rotenone atau parakuat, dan herbisida, seperti Agent Orange [61]. [62] [63] langkah-langkah tidak langsung paparan, seperti tinggal di lingkungan pedesaan, telah ditemukan untuk meningkatkan risiko PD. [63] logam berat telah diusulkan paparan menjadi faktor risiko, melalui akumulasi mungkin dalam substantia nigra;. Namun, studi tentang masalah ini telah meyakinkan [61]

Faktor pelindung
Merokok telah dikaitkan dengan penurunan risiko memiliki PD. Risiko perokok memiliki PD dapat dikurangi turun ke ketiga ketika dibandingkan non-perokok [61]. Dasar untuk efek ini tidak diketahui, tetapi kemungkinan mencakup efek dari nikotin sebagai stimulan dopamin. [61] Asap tembakau mengandung senyawa yang bertindak sebagai inhibitor MAO yang mungkin juga berkontribusi terhadap efek ini [64] konsumsi Kafein juga melindungi terhadap PD. [65] Antioksidan, seperti vitamin C dan D, telah diusulkan untuk melindungi terhadap penyakit, tetapi hasil penelitian telah. bertentangan dan tidak ada efek positif telah terbukti. [61] Hasil mengenai asam lemak dan lemak telah bertentangan, dengan berbagai penelitian melaporkan efek protektif, risiko-meningkatkan efek atau tanpa efek. [61] Akhirnya ada indikasi awal dari suatu kemungkinan peran protektif estrogen dan anti-inflamasi [61].

Sejarah

Sebuah foto dari 1893 Jean-Martin Charcot, yang membuat kontribusi penting untuk memahami penyakit dan diusulkan namanya sekarang menghormati James Parkinson

Sumber-sumber awal Beberapa, termasuk papirus Mesir, sebuah risalah medis Ayurvedic, Alkitab, atau tulisan Galen, menggambarkan gejala menyerupai orang-orang PD [66]. Setelah Galen tidak ada referensi jelas terkait dengan PD sampai abad ke-17. [66] Dalam abad 17 dan 18, beberapa penulis menulis tentang unsur-unsur dari penyakit, termasuk Sylvius, Gaubius, Hunter dan Chomel. [66] [67] [68]

Pada 1817 seorang dokter Inggris, James Parkinson, menerbitkan esainya melaporkan enam kasus agitans kelumpuhan. [69] Sebuah Esai tentang Cerebral Sambil menggambarkan karakteristik tremor istirahat, postur abnormal dan kiprah, kelumpuhan dan kekuatan otot berkurang, dan cara yang Penyakit berlangsung dari waktu ke waktu. [69] [70] ahli saraf Awal yang membuat penambahan lebih lanjut untuk pengetahuan tentang penyakit ini termasuk Trousseau, Gowers, Kinnier Wilson dan Erb, dan terutama Jean-Martin Charcot, yang penelitiannya antara 1868 dan 1881 adalah tengara dalam pemahaman penyakit ini [69] Di antara kemajuan lain., dia membuat perbedaan antara kekakuan, kelemahan dan bradykinesia. [69] Ia juga memperjuangkan penggantian nama penyakit untuk menghormati James Parkinson. [69]

Pada tahun 1912 Frederic Lewy dijelaskan partikel mikroskopis dalam otak yang terkena, kemudian dinamai “badan Lewy” [69] Pada tahun 1919 melaporkan bahwa Konstantin Tretiakoff substantia nigra adalah struktur otak utama yang terkena dampak, namun temuan ini tidak diterima secara luas sampai dikonfirmasi oleh lebih lanjut. studi yang diterbitkan oleh Rolf Hassler tahun 1938 [69]. Perubahan biokimia yang mendasari di otak diidentifikasi pada tahun 1950, terutama disebabkan oleh Arvid Carlsson pekerjaan pada neurotransmitter dopamin dan perannya di PD. [71] Pada tahun 1997, alfa- synuclein ditemukan menjadi komponen utama dari badan Lewy. [27]

Antikolinergik dan pembedahan (lesioning dari jalur kortikospinalis atau beberapa struktur basal ganglia) adalah pengobatan hanya sampai kedatangan levodopa, yang mengurangi penggunaan mereka secara dramatis [67] [72]. Levodopa pertama kali disintesis pada tahun 1911 oleh Casimir Funk, namun itu mendapat sedikit perhatian sampai pertengahan abad ke-20 [71] Ini masuk praktek klinis pada tahun 1967 dan membawa sebuah revolusi dalam manajemen PD [71] [73]. Dengan stimulasi otak 1980-an yang mendalam muncul sebagai pengobatan mungkin.. [ 74]

Penelitian arah

Ada sedikit prospek dramatis perawatan PD baru yang diharapkan dalam jangka waktu yang singkat [75] arah penelitian Saat ini aktif meliputi mencari model hewan baru dari penyakit dan studi tentang manfaat potensi terapi gen, transplantasi stem sel dan agen saraf.. [26]

Hewan model
PD tidak diketahui terjadi secara alami dalam spesies selain manusia, meskipun model hewan yang menunjukkan beberapa fitur penyakit yang digunakan dalam penelitian. Munculnya gejala parkinsonian dalam kelompok pecandu narkoba di awal 1980-an yang mengkonsumsi terkontaminasi batch dari candu sintetis MPPP menyebabkan penemuan MPTP kimia sebagai agen yang menyebabkan sindrom parkinsonian dalam primata non-manusia serta manusia [76]. Lain dominan racun model berbasis mempekerjakan rotenone insektisida, herbisida paraquat dan fungisida maneb [77]. Model didasarkan pada racun yang paling sering digunakan pada primata. Hewan model transgenik yang meniru berbagai aspek dari PD telah dikembangkan. [78]

 Terapi gen
Terapi gen melibatkan penggunaan virus tidak menular untuk antar-jemput gen menjadi bagian dari otak. Gen yang digunakan menyebabkan produksi enzim yang membantu untuk mengelola gejala PD atau melindungi otak dari kerusakan lebih lanjut [26]. [79] Pada tahun 2010 ada empat uji klinis menggunakan terapi gen pada PD. [26] belum ada efek samping penting dalam ujicoba tersebut meskipun kegunaan klinis terapi gen masih belum diketahui [26] Salah satu hasil positif yang dilaporkan pada tahun 2011.. [80]

Perawatan saraf

Sementara beberapa senyawa kimia seperti GDNF (struktur kimia digambarkan) telah diusulkan sebagai neuroprotectors di PD, belum terbukti kemanjurannya.

Investigasi pada pelindung saraf berada di garis depan PD penelitian. Beberapa molekul telah diusulkan sebagai perawatan potensial. [26] Namun, tidak satupun dari mereka telah meyakinkan menunjukkan untuk mengurangi degenerasi [26]. Agen saat ini sedang diselidiki termasuk anti-apoptotics (omigapil, CEP-1347), antiglutamatergics, inhibitor monoamine oxidase ( selegiline, rasagiline), promitochondrials (koenzim Q10, creatine), calcium channel blockers (isradipine) dan faktor pertumbuhan (GDNF) [26] Penelitian praklinis juga menargetkan alpha-synuclein.. [75]

 Neural transplantasi
Sejak awal 1980-an, janin, babi, jaringan karotis atau retina telah digunakan dalam transplantasi sel, di mana sel terdisosiasi yang disuntikkan ke dalam substantia nigra dengan harapan bahwa mereka akan menggabungkan diri ke otak dengan cara yang menggantikan dopamin- memproduksi sel-sel yang telah hilang [26]. Meskipun ada bukti awal yang memproduksi dopamin mesensefalik transplantasi sel yang menguntungkan, double-blind uji coba sampai saat ini menunjukkan bahwa transplantasi sel tidak menghasilkan manfaat jangka panjang. [26] Sebuah masalah yang signifikan tambahan pelepasan dopamin kelebihan oleh jaringan transplantasi, menyebabkan distonia [81]. Transplantasi sel induk adalah target penelitian terbaru, karena sel-sel induk yang mudah untuk memanipulasi dan sel induk yang ditransplantasikan ke dalam otak tikus dan monyet telah ditemukan untuk bertahan hidup dan mengurangi kelainan perilaku [26] [82]. Namun demikian, penggunaan sel induk janin kontroversial. [26] Telah diusulkan bahwa perawatan yang efektif dapat dikembangkan dalam cara yang kurang kontroversial oleh penggunaan sel induk pluripotent yang diambil dari orang dewasa. [ 26]

Masyarakat dan budaya

Muhammad Ali pada usia 64 pada tahun 2006. Dia telah menunjukkan tanda-tanda parkinson sejak usia 38.

Biaya
Biaya PD untuk masyarakat yang tinggi, tetapi sulit untuk menghitung persis karena kesulitan metodologis dalam penelitian dan perbedaan antara negara-negara [83]. Biaya tahunan di Inggris diperkirakan antara 449 juta dan 3.3 miliar pounds, sedangkan biaya per pasien per tahun di AS mungkin sekitar $ 10.000 dan total beban sekitar 23 miliar dolar [83]. Bagian terbesar dari biaya langsung berasal dari rawat inap dan panti jompo, sedangkan pangsa datang dari obat secara substansial lebih rendah. [83] Tidak Langsung biaya tinggi, karena produktivitas berkurang dan beban pada pengasuh [83] Di samping biaya ekonomi, PD mengurangi kualitas hidup dari orang-orang dengan penyakit dan pengasuh mereka.. [83]

 Pembelaan
April 11, ulang tahun James Parkinson, telah ditunjuk sebagai hari penyakit dunia Parkinson [69] [84] Sebuah bunga tulip merah dipilih oleh beberapa organisasi internasional sebagai simbol penyakit pada tahun 2005:. Itu merupakan kultivar James Tulip Parkinson , terdaftar pada tahun 1981 oleh seorang holtikultura Belanda [84] organisasi Advokasi pada penyakit termasuk National Parkinson Foundation, yang telah memberikan lebih dari $ 155,000,000 dalam pelayanan perawatan, penelitian dan dukungan sejak 1982., [85] Penyakit Yayasan Parkinson, yang telah memberikan lebih dari $ 90 juta untuk penelitian dan $ 37.000.000 untuk program pendidikan dan advokasi sejak didirikan pada tahun 1957 oleh William Hitam; [86] [87] American Parkinson Penyakit Asosiasi, didirikan pada tahun 1961; [88] dan Parkinson Eropa Penyakit Asosiasi, didirikan pada tahun 1992 [89].

Terkemuka kasus
Artikel utama: Daftar orang didiagnosis dengan penyakit Parkinson
Di antara banyak orang terkenal dengan PD, orang yang telah sangat meningkatkan kesadaran masyarakat dari penyakit adalah aktor Michael J. Fox. Fox didiagnosis pada tahun 1991 ketika ia berumur 30, tapi kondisinya dirahasiakan dari publik selama tujuh tahun [90] Ia telah menulis dua buku yg berhubungan dgn riwayat hidup sendiri di mana perjuangannya melawan penyakit tersebut memainkan peran utama, [91]. Dan muncul sebelum Kongres Amerika Serikat tanpa obat untuk menggambarkan efek dari penyakit [91]. Michael J. Fox Foundation bertujuan untuk mengembangkan obat untuk penyakit Parkinson. Dalam beberapa tahun terakhir ini telah menjadi penggalang dana utama Parkinson di Amerika Serikat, menyediakan 140 juta dolar dalam pendanaan penelitian antara 2001 dan 2008 [91]. Kerja Fox membuatnya menjadi nama salah satu dari 100 orang “yang kekuasaannya, bakat atau contoh moral mengubah dunia “pada tahun 2007 oleh majalah Time, [90] dan ia menerima gelar doktor kehormatan dalam kedokteran dari Karolinska Institutet atas kontribusi untuk penelitian dalam penyakit Parkinson [92]. lain yayasan yang mendukung riset Parkinson didirikan oleh pengendara sepeda profesional Davis Phinney. [93] Para Davis Phinney Yayasan berusaha untuk memperbaiki kehidupan mereka yang hidup dengan penyakit Parkinson dengan menyediakan mereka dengan informasi dan alat-alat [94]. Muhammad Ali telah disebut “pasien yang paling terkenal di dunia Parkinson” itu. [95] Dia adalah 42 pada Diagnosis meskipun dia sudah menunjukkan tanda-tanda Parkinson ketika ia 38. [96] Namun demikian, apakah ia telah PD atau sindrom parkinsonian disebabkan oleh tinju masih merupakan pertanyaan terbuka
  
  
  
  
  
  
  
  
  
  

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The end @ copyright Dr Iwan suwandy 2011