Parkinson's disease

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"Parkinson's" redirects here. For other uses, see Parkinson's (disambiguation).
Parkinson's
Classification and external resources

Illustration of the Parkinson disease by Sir William Richard

Gowers from A Manual of Diseases of the Nervous System in
1886

Parkinson's disease (also known as Parkinson's, Parkinson disease or PD) is a degenerative

disorder of the central nervous system that often impairs the sufferer's motor skills, speech, and
other functions.[1]

Parkinson's disease belongs to a group of conditions called movement disorders. It is

characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and a
loss of physical movement (akinesia) in extreme cases. The primary symptoms are the results of
decreased stimulation of the motor cortex by the basal ganglia, normally caused by the
insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of
the brain (specifically the substantia nigra). Secondary symptoms may include high level
cognitive dysfunction and subtle language problems. PD is both chronic and progressive.

PD is the most common cause of chronic progressive parkinsonism, a term which refers to the
syndrome of tremor, rigidity, bradykinesia and postural instability. PD is also called "primary
parkinsonism" or "idiopathic PD" (classically meaning having no known cause). While many
forms of parkinsonism are idiopathic, "secondary" cases may result from toxicity most notably of
drugs, head trauma, or other medical disorders. The disease is named after English apothecary
James Parkinson, who made a detailed description of the disease in his essay: "An Essay on the
Shaking Palsy" (1817).

[edit] Classification
The term Parkinsonism is used for symptoms of tremor, stiffness, and slowing of movement
caused by loss of dopamine. "Parkinson's disease" is the synonym of "primary parkinsonism",
i.e., isolated parkinsonism due to a neurodegenerative process without any secondary systemic
cause. In some cases, it would be inaccurate to say that the cause is "unknown", because a small
proportion is caused by genetic mutations. It is possible for a patient to be initially diagnosed
with Parkinson's disease but then to develop additional features, requiring revision of the
diagnosis.

There are other disorders that are called Parkinson-plus diseases. These include: multiple system
atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).
Some include dementia with Lewy bodies (DLB) — while idiopathic Parkinson's disease
patients also have Lewy bodies in their brain tissue, the distribution is denser and more
widespread in DLB. Even so, the relationship between Parkinson disease, Parkinson disease with
dementia (PDD), and dementia with Lewy bodies (DLB) might be most accurately
conceptualized as a spectrum, with a discrete area of overlap between each of the three disorders.
The cholinesterase inhibiting medications have shown preliminary efficacy in treating the
cognitive, psychiatric, and behavioral aspects of the disease of both PD and DLB. The natural
history and role of Lewy bodies is little understood.

These Parkinson-plus diseases may progress more quickly than typical idiopathic Parkinson
disease. If cognitive dysfunction occurs before or very early in the course of the movement
disorder, then DLBD may be suspected. Early postural instability with minimal tremor,
especially in the context of ophthalmoparesis, should suggest PSP. Early autonomic dysfunction,
including erectile dysfunction and syncope, may suggest MSA. The presence of extreme
asymmetry with patchy cortical cognitive defects such as dysphasia and apraxias (especially with
"alien limb" phenomena) should suggest CBD.

The usual anti-Parkinson's medications are typically either less effective or completely
ineffective in controlling symptoms; patients may be exquisitely sensitive to neuroleptic
medications like haloperidol, so correct differential diagnosis is important.

Essential tremor may be mistaken for Parkinson's disease, but lacks all other features besides
tremor, and has particular characteristics distinguishing it from Parkinson's disease, such as
improvement with beta blockers and alcoholic beverages.[1]

Wilson's disease (hereditary copper accumulation) may present with parkinsonian features;
young patients presenting with parkinsonism or any other movement disorder are frequently
screened for this rare condition, because it may respond to medical treatment. Typical tests are
liver function, slit lamp examination for Kayser-Fleischer rings, and serum ceruloplasmin levels.

[
edit] Signs and symptoms
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, cognitive and neurobehavioral problems, and sensory and
sleep difficulties, are also common but are under-appreciated.[1]

[edit] Motor

Further information: Parkinsonian gait

Four motor symptoms are considered cardinal in PD: tremor, rigidity, bradykinesia and postural
instability.[1] Tremor is the most apparent and well-known symptom.[1] It is most commonly 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 extremity and is typically unilateral at
onset becoming bilateral later.[1] Though around 30% of PD sufferers do not have tremor at
disease onset most of them would develop it along the course of the disease.[1] Rigidity is due to
joint stiffness and increased muscle tone, which combined with a resting tremor produce a
ratchety, "cogwheel rigidity" when the limb is passively moved.[1] Rigidity may be associated
with joint pain, such pain being a frequent initial manifestation of the disease.[1] Bradykinesia
(slowness of movement) is the most characteristic clinical feature of PD and it produces
difficulties not only with the execution of a movement but also with its planning and initiation.[1]
The performance of sequential and simultaneous movements is also hindered.[1] In the late stages
of the disease postural instability is typical, which leads to impaired balance and falls.[1]

PD motor symptomatology is not limited to these four symptoms. Gait and posture disturbances
such as decreased arm swing, a forward-flexed posture and the use of small steps when walking;
speech and swallowing disturbances; and other symptoms such as a mask-like face expression or
a small handwriting are only examples of the ample range of common motor problems that can
appear with the disease.[1]

[edit] Neuropsychiatric

Parkinson's disease causes neuropsychiatric disturbances, which include mainly cognition, mood
and behavior problems and can be as disabling as motor symptoms.[1]

Cognitive disturbances occur even in the initial stages of the disease in some cases.[2] A very high
proportion of sufferers will have mild cognitive impairment as the disease advances.[1] Most
common cognitive deficits in non-demented patients are executive dysfunction, which translates
into impaired set shifting, poor problem solving, and fluctuations in attention among other
difficulties; slowed cognitive speed, memory problems; specifically in recalling learned
information, with an important improvement with cues; and visuospatial skills difficulties, which
are seen when the person with PD is for example asked to perform tests of facial recognition and
perception of line orientation.[2]

Deficits tend to aggravate with time, developing in many cases into dementia. A person with PD
has a sixfold increased risk of suffering dementia,[1] and the overall rate in people with the
disease is around 30%.[2] Moreover, prevalence of dementia increases in relation to disease
duration, going up to 80%.[2] Dementia has been associated with a reduced quality of life in
disease sufferers and caregivers, increased mortality and a higher probability of attending a
nursing home.[2]

Cognitive problems and dementia are usually accompanied by behavior and mood alterations,
although these kind of changes are also more common in those patients without cognitive
impairment than in the general population. Most frequent mood difficulties include depression,
apathy and anxiety.[1] Obsessive–compulsive behaviors such as craving, binge eating,
hypersexuality, pathological gambling, or other, can also appear in PD, and have been related to
a dopamine dysregulation syndrome associated with the medications for the disease.[1] Psychotic
symptoms are common in later PD. Symptoms of psychosis are either hallucinations, or
delusions.[3]

[edit] Other

In addition to cognitive and motor symptoms PD can impair other body functions. Sleep
problems can be worsened by medications for PD, but they are a core feature of the disease.[1]
They can manifest as excessive daytime somnolence, disturbances in REM sleep or insomnia.[1]
The autonomic system is altered which can lead for example to orthostatic hypotension, oily skin
and seborrheic dermatitis, excessive sweating, urinary incontinence and altered sexual function.[1]
Constipation and gastric dysmotility can be severe enough to endanger comfort and health.[4] PD
is also related to different ophthalmological abnormalities such as decreased blink rate and
alteration in the tear film, leading to irritation of the eye surface, abnormalities in ocular pursuit
and saccadic movements and limitations in the upward gaze.[1] Changes in perception include
reduced sense of smell and sensation of pain and paresthesias.[1]

[edit] Causes
Most people with Parkinson's disease are described as having idiopathic Parkinson's disease
(having no specific known cause). A small proportion of cases is known to be originated in
genetic factors.

[edit] Genetic

Positive Alpha-Synuclein staining of a Lewy body in a patient with Parkinson's disease.

PD traditionally has been considered a non-genetic disorder, however at least between 5 and
10% of the patients are now known to have monogenic forms of the disease.[5] Other genes act as
risk factors for sporadic cases of the disease.

A number of specific genetic mutations causing Parkinson's disease have been discovered. Genes
conclusively identified are Alpha-synuclein (SNCA), ubiquitin carboxy-terminal hydrolase L1
(UCH-L1), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin) , PTEN-induced
putative kinase 1 (PINK1), DJ-1 and ATP13A2.[5][6] With the exception of LRRK2 they account
for a small minority of cases of PD.[6] Most studied PD-related genes are SNCA and LRRK2.

The role of the SNCA gene is central in the pathophysiology of PD, since the Alpha-synuclein
protein is the main component of Lewy bodies, which are present in this and other diseases.[5]
Missense mutations of the gene and duplications and triplications of the locus containing it have
been found in different groups with familial PD.[5] Missense mutations are very rare with few
families found in all the world, most with a common ancestor.[5] On the other hand
multiplications of the SNCA locus account for around 2% of familial cases.[5] Additionally
multiplications have age-dependent or incomplete penetrance, since they have also been found in
non symptomatic carriers.[5]

The LRRK2 gene (PARK8) encodes for a protein called dardarin. The name dardarin comes
from a basque word for tremor since such gene was first identified in families from England and
the north of Spain.[6] LRRK is the most common cause known of familial and sporadic PD, with
mutations in this gene in up to 10% of the patients with a family history of the disease and 3% of
sporadic cases.[5][6] Although more than 40 different mutations of the gene have been found, one
of them (G2019S) appears in 5% of the familial cases and 2% of the sporadic ones in Europe.[5]
Nevertheless prevalence of this mutation varies greatly with ethnicity, being for example rare in
Asia but very common in PD cases of northern Africa and among Ashkenazi Jews[5] The
penetrance of the G2019S mutation ranges between 28% at age 60 and 75% at age 80 with sex
having no effect.[5]

Other mutations in at least three of the causative genes of the famililial forms of the disease have
been found to be a risk factor for the so-called sporadic PD. The three are SNCA, LRRK2 and
GBA.[5] Genome-wide association studies; which search for mutated alleles with low penetrance
in sporadic cases; have yielded few positive results although the number of such studies has been
scarce and their size small.[5]

[edit] Pathophysiology

Circuits of the basal ganglia in the normal state.

Circuits of the basal ganglia in Parkinson's disease, resulting from decreased activity of the pars
compacta region of the substantia nigra. Larger and smaller arrows refer to pathways with
increased and decreased activity, respectively, in Parkinson's disease.
Circuits of the basal ganglia in the normal state (left) and PD (right). Substantia nigra is seen
at bottom right. Pictures show 2 coronal slices that have been superimposed to include the
involved basal ganglia structures. + and - signs at the point of the arrows indicate respectively
whether the pathway is excitatory or inhibitory in effect. Green arrows refer to excitatory
glutamatergic pathways, red arrows refer to inhibitory GABAergic pathways and turquoise
arrows refer to dopaminergic pathways that are excitatory on the direct pathway and inhibitory
on the indirect pathway. Dis-inhibitory pathways are in effect excitatory on the feedback to the
cortex, while dis-dis-inhibitory pathways are inhibitory.
Black-staining granules of neuromelanin within neurons of the substantia nigra

The main pathological characteristic is cell death in the substantia nigra and more specifically the
ventral part of the pars compacta, affecting up to 70% of the cells by death time.[6] The
mechanisms by which the brain cells in Parkinson's are lost are varied.[7] One mechanism
consists of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the
damaged cells. This protein accumulation forms inclusions called Lewy bodies.[6] 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, being at this stage
patients asymptomatic. As the disease evolves Lewy bodies later attain the substantia nigra, areas
of the midbrain and basal prosencephalon and finally reach areas of the neocortex.[6] Other cell-
death mechanisms include proteosomal and lysosomal system dysfunction, and reduced
mitochondrial activity.[7]

There are four major dopamine pathways in the brain; the nigrostriatal pathway, referred to
above, mediates movement and is the most conspicuously affected in early Parkinson's disease.
The other pathways are the mesocortical, the mesolimbic, and the tuberoinfundibular. Disruption
of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric
pathology associated with Parkinson's disease.

The direct pathway facilitates movement and the indirect pathway inhibits movement, thus the
loss of these cells leads to a hypokinetic movement disorder. The lack of dopamine results in
increased inhibition of the ventral anterior nucleus of the thalamus, which sends excitatory
projections to the motor cortex, thus leading to hypokinesia The symptoms of Parkinson's
disease result from the greatly reduced activity of pigmented dopamine-secreting (dopaminergic)
cells in the pars compacta region of the substantia nigra (literally "black substance"). These
neurons project to the striatum and their loss leads to alterations in the activity of the neural
circuits within the basal ganglia that regulate movement. In essence, GABA/ Substance P of the
direct pathways diminish, leading to less inhibition of the pars reticulata and internal globus
palidus and an inhibition of the indirect pathway by way of GABA/ enkaphalins.

Excessive accumulations of iron, which are toxic to nerve cells, are also typically observed in
conjunction with the protein inclusions. Iron and other transition metals such as copper bind to
neuromelanin in the affected neurons of the substantia nigra. Neuromelanin may be acting as a
protective agent. The most likely mechanism is generation of reactive oxygen species.[8][9] Iron
also induces aggregation of synuclein by oxidative mechanisms.[10] Similarly, dopamine and the
byproducts of dopamine production enhance alpha-synuclein aggregation. The precise
mechanism whereby such aggregates of alpha-synuclein damage the cells is not known. The
aggregates may be merely a normal reaction by the cells as part of their effort to correct a
different, as-yet unknown, insult. Based on this mechanistic hypothesis, a transgenic mouse
model of Parkinson's has been generated by introduction of human wild-type alpha-synuclein
into the mouse genome under control of the platelet-derived-growth factor-β promoter.[11]

A recent view of Parkinson's disease implicates specialized calcium channels that allow
substantia nigra neurons, but not most neurons, to repetitively fire in a "pacemaker" like pattern.
The consequent flooding of calcium into these neurons may aggravate damage to mitochondria
and may cause cell death. One study has found that, in experimental animals, treatment with a
calcium channel blocker isradapine had a substantial protective effect against the development of
Parkinson's disease.[12]

[edit] Diagnosis

18F PET scan shows decreased dopamine activity in the basal ganglia, a pattern which aids in
diagnosing Parkinson's disease.

Typically, the diagnosis is based on medical history and neurological examination.[1] The
physician interviews and observes the patient in the search of the cardinal motor symptoms of
the disease, while also attending to other symptoms that would exclude the diagnosis of PD.[1]
Response to levodopa is another sign pointing towards PD.[1] However there is no definitive test
for diagnosis although finding lewy bodies during autopsy has been traditionally considered the
gold standard for diagnosis.[1] Common presentations of the disease are usually easily diagnosed,
however the disease can be difficult to diagnose accurately, especially in its early stages, since
parkinsonisms can occur due to a range of pathologies differing from PD.[1]

Medical organizations have created diagnostic criteria to ease and standardize the diagnostic
process especially in the first stages of the disease. The most widely known are those by the UK
Parkinson’s Disease Society Brain Bank and the National Institute of Neurological Disorders and
Stroke.[1] For example the PD Society Brain Bank criteria require in the first place the person to
suffer from slowness of movement (bradykinesia) and either rigidity, rest tremor or postural
instability. Secondly other possible causes for symptoms have to be ruled out. Finally the person
would have to have 3 or more of the following during onset or evolution: unilateral onset, rest
tremor, progression, asymmetry of motor symptoms, response to levodopa during at least 5
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 between 75 and
90% with specialists such as neurologists having higher rates.[1]

Differential diagnosis includes other kind of tremors and also other causes of parkinsonism.[13]
Other tremors include postural and action tremors or intention tremor.[13] Other causes of a
parkinsonian syndrome are Alzheimer's disease, multiple cerebral infarction, drug induced
parkinsonism, and other degenerative parkinsonian syndromes such as progressive supranuclear
palsy and multiple system atrophy.[13]

Computed tomography (CT) and Magnetic resonance imaging (MRI) brain scans of people with
PD usually appear normal.[14] These techniques are nevertheless useful for diagnosis to rule out
other diseases which can be secondary causes of parkinsonism such as basal ganglia tumors,
vascular pathology and hydrocephalus.[14] 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.[14] Dopaminergic function in the basal ganglia
can be measured with the help of different PET and SPECT radiotracers. Examples are ioflupane
(123I) (trade name DaTSCAN) and iometopane (Dopascan) for SPECT or 18F for PET.[14] A
pattern of reduced dopaminergic activity in the basal ganglia, can aid in diagnosing PD.[14]
[edit] Management
Main article: Treatments of Parkinson's Disease

At present, there is no cure for Parkinson's disease, but medications, surgery and
multidisciplinary management can provide relief from the symptoms.

PD is a chronic disorder that requires broad-based management including patient and family
education, support group services, general wellness maintenance, physiotherapy, exercise, and
nutrition.

Main families of drugs useful for motor symptoms of PD are Levodopa, dopamine agonists and
MAO-B inhibitors.[15] Regarding medications the treatment approach varies depending on the
stage of the person with the disease. Two phases are usually considered: an initial phase in which
the PD sufferer has already developed some disability for which he needs pharmacological
treatment, and a second stage in which the patient develops motor complications related to
levodopa usage.[15] Treatment in the initial state aims to attain an equilibrium between reduced
dopaminergic therapy and good management of symptoms. Additionally L-dopa beginning is
delayed using other medications such as MAO-B inhibitors and dopamine agonists so the later
PD stage is retarded.[15] In the second stage the aim is to reduce symptoms while controlling
fluctuations between on and off periods. Sudden withdrawals from medication, and overuse by
some patients, also have to be controlled.[15]

[edit] Levodopa

Stalevo for treatment of Parkinson's disease

Circuits of the basal ganglia in treatment of Parkinson's disease. Levodopa, dopamine agonists
and MAO-B inhibitors stimulate excitatory signals from the thalamus to the cortex by effects on
the striatum, compensating for decreased dopaminergic signals from substantia nigra (seen at
bottom right).

Levodopa (or L-DOPA) has been the most widely used treatment for over 30 years.[15] L-DOPA
is transformed into dopamine in the dopaminergic neurons by dopa-decarboxylase.[15] Since
motor symptoms of PD are produced by a lack of dopamine in the substantia nigra the
administration of L-dopa temporarilly diminishes the motor symptomatology.[15]

Only 5-10% of L-DOPA crosses the blood-brain barrier. The remaining L-DOPA is often
metabolised to dopamine elsewhere, causing a wide variety of side effects including nausea,
dyskinesias and stiffness.[15] Carbidopa and benserazide are peripheral dopa decarboxylase
inhibitors.[15] They help to prevent the metabolism of L-DOPA before it reaches the
dopaminergic neurons and therefore reduce side effects. They are generally given as combination
preparations with levodopa.[15] Existing preparations are carbidopa/levodopa (co-careldopa, trade
names Sinemet, Parcopa, Atamet) and benserazide/levodopa]] (co-beneldopa, trade name
Madopar).

There are controlled release versions of Sinemet and Madopar that spread out the effect of the
levodopa. Duodopa is a combination of levodopa and carbidopa. Slow-release levodopa
preparations have not shown an increased control of motor symptoms or motor complications
when compared to immediate release preparations.[15]

Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects
of levodopa.[15] It has been used to complement levodopa. However, due to its possible side
effects such as liver failure, it's limited in its availability.[15] A similar drug, entacapone has not
been shown to cause significant alterations of liver function and maintains adequate inhibition of
COMT over time.[15] Entacapone is available for treatment alone (COMTan) or combined with
carbidopa and levodopa (Stalevo).[15]
Due to feedback inhibition, levodopa results in a reduction in the endogenous formation of L-
dopa, and so eventually becomes counterproductive.[citation needed] 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.[15] When this occurs PD
sufferers change fastly from stages with good response to medication and few symptoms ("on"
state) to phases with no response to medication and important motor symptoms ("off" state).[15]
For this reason levodopa doses are maintained as low as possible while maintaining
functionality.[15] Delaying the initiation of dopatherapy, using instead alternatives for some time,
is also common practice.[15] A former strategy to reduce motor complications was to withdraw
patients from L-dopa for some time. It is discouraged now since it can bring dangerous side
effects such as neuroleptic malignant syndrome.[15] Most people will eventually need levodopa
and later develop motor complications.[15]

[edit] Dopamine agonists

Dopamine agonists in the brain have a similar effect to levodopa since they bind to dopaminergic
post-synaptic receptors.[15] Dopamine agonists were initially used for patients experiencing on-off
fluctuations and dyskinesias as a complementary therapy to levodopa but they are now mainly
used on their own as an initial therapy for motor symptoms with the aim of delaying motor
complications.[15][16] When used in late PD they are useful at reducing the off periods.[15]

Agonists produce significant, although mild, side effects including somnolence, hallucinations,
insomnia, nausea, and constipation.[15] Sometimes side effects appear even at a the minimal
clinically efficacious dose, leading the physician to search for a different agonist or kind of drug.
[15]
When compared with levodopa, while they delay motor complications they have greater side
effects and control worse symptoms.[15] Apomorphine, which is a non-orally administered
dopamine agonist, may be used to reduce off periods and dyskinesia in late PD.[15] It is
administered by intermitent injections or continuous subcutaneous infusions.[15] Since secondary
effects such as confusion and hallucinations are not rare it has been recommended that patients
under apomorphine treatment should be closely monitored.[15]

Dopamine agonists initially act by stimulating some of the dopamine receptors. However, they
cause the dopamine receptors to become progressively less sensitive, thereby eventually
increasing the symptoms.[citation needed] Dopamine agonists include bromocriptine, pergolide,
pramipexole, ropinirole , piribedil, cabergoline, apomorphine, and lisuride.[citation needed]

[edit] MAO-B inhibitors

MAO-B inhibitors (Selegiline and rasagiline) increase the level of dopamine in the basal ganglia
by blocking its metabolization. They inhibit monoamine oxidase-B (MAO-B) which breaks
down dopamine secreted by the dopaminergic neurons. Therefore reducing MAO-B results in
higher quantities of L-DOPA in the striatum.[15] Similarly to dopamine agonists, MAO-B
inhibitors improve motor symptoms and delay the need of taking levodopa when used as
monotherapy in the first stages of the disease but produce more adverse effects and are less
effective than levodopa. Evidence on their efficacy in the advanced stage is reduced although it
points towards them being useful to reduce fluctuations between on and off periods.[15] Although
an initial study had as result that selegiline in combination with levodopa increased the risk of
death this has been later disproven.[15]

[edit] Other drugs

There is some indication that other drugs such as amantadine and anticholinergics may be useful
as treatment of motor symptoms in early and late PD, but since quality of evidence on efficacy is
reduced they are not first choice treatments.[15] In addition to motor PD is accompanied by an
ample range of different symptoms. Different compounds are used to improve some of these
problems.[17] Examples are the use of clozapine for psychosis, cholinesterase inhibitors for
dementia and modafinil for day somnolence.[17][18]

[edit] Surgery and deep brain stimulation

Illustration showing an electrode placed deep seated in the brain

Treating motor symptomatology in Parkinson's disease with surgery was once a common
practice, but after the discovery of levodopa, number of surgeries was reduced.[19] Studies in the
past few decades have led to great improvements in surgical techniques, and surgery is again
being used in people with advanced PD for whom drug therapy is no longer sufficient.[19] Deep
brain stimulation (DBS) is presently the most used surgical mean of treatment but other surgical
therapies consisting in producing lesions in specific subcortical areas are also effective.[19] DBS
involves the implantation of a medical device called a brain pacemaker, which sends electrical
impulses to specific parts of the brain. Target areas for DBS or lesions include the thalamus, the
globus pallidus (the lesion technique being called pallidotomy) or the subthalamic nucleus.[19]
[edit] Rehabilitation

There is partial evidence that speech or mobility problems can improve with rehabilitation
although studies are still scarce and of low quality.[20][21] Regular physical exercise and/or therapy
can be beneficial to the patient for maintaining and improving mobility, flexibility, strength, gait
speed, and quality of life;[21] Exercise may also improve constipation.[4] One of the most widely
practiced treatment for speech disorders associated with Parkinson's disease is the Lee Silverman
Voice Treatment (LSVT), which focuses on increasing vocal loudness and has an intensive
approach of one month.[20][22] Speech therapy and specifically LSVT may improve voice and
speech function.[20] Occupational therapy (OT) aims to promote health and quality of life by
helping people with the disease to participate in as many activities of their daily living as
possible.[20] Number of studies and quality of them regarding the effectiveness of OT is poor,
although there is some indication that it may improve motor skills and quality of life for the
duration of the therapy.[20][23]

[edit] Diet

Muscles and nerves that control the digestive process may be affected by PD, therefore, it is
common for patients to experience constipation and gastroparesis (food remaining in the stomach
for a longer period of time than normal).[4] A balanced diet is hence recommended to help
improve digestion. Diet should include high-fiber foods and plenty of water.[4] Levodopa and
proteins use the same transportation system in the intestine and the blood-brain barrier,
competing between them for access.[4] When taken together the consequences of such
competition is a reduced effectiveness of the drug.[4] Therefore when levodopa is introduced
excessive proteins are discouraged, while in advanced stages additional intake of low-protein
products such as bread or pasta is recommended for similar reasons.[4] To minimize interaction
with proteins levodopa is recommended to be taken 30 minutes before meals.[4] At the same time,
regimens for PD patients restrict proteins during breakfast and lunch and are usually taken at
dinner.[4] As the disease advances dysphagia may appear. In such cases specific measures include
the use of thickening agents for liquid intake, special postures when eating and gastrostomy in
the worst cases.[4]

[edit] Alternative Treatments

Different nutrients have been proposed as possible treatments of PD; however there is no
evidence that vitamin or food additives improve PD symptoms.[24] There is not enough evidence
to suggest that acupuncture, and practice of qigong or tai chi have any effect on PD symptoms.[25]
[26][27]
Fava and velvet beans are natural sources of L-DOPA and are taken by many patients.
While they have shown some effectiveness,[28] their intake is not free of risks. Life threatening
adverse reactions have been described, such as the neuroleptic malignant syndrome.[29][30]
[edit] Prognosis
See also: Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale

Disability-adjusted life year for parkinson disease per 100,000 inhabitants in 2004.

     no data      less than 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      more than 80

PD progresses with time. If not treated motor symptoms have an aggressive advance at the
beginning of the disease with an slower advance later on the disease course: untreated patients
are expected to loose independent ambulation after 8 years and be bedridden after 10 years.[31]
However it is not common to find untreated people nowadays and medication has improved the
prognosis of motor symptoms, while at the same time it is also a new source of disability due to
the undesired effects of L-dopa after years of use.[31] Different studies of the history of the
disease on people taking L-Dopa have found that the mean progression of symptoms to an stage
of high dependency of subjects may take around 15 years.[31] However it is hard to predict what
course the disease will take for an individual.[31] Age is the best predictor of disease progression.
[7]
Rate of motor decline is greater in those with less impairment at diagnosis while cognitive
impairment is more frequent in those who are over 70 years of age at symptoms onset.[7]

Since current therapies improve motor symptoms, disability at present is mainly related to non-
motor features of the disease.[7] Nevertheless the relationship between disease progression and
disability is not linear. At first disability is related to motor symptoms and specially motor
complications, which appear in up to 50% of the patients after 5 years of L-Dopa usage.[31] As the
disease advances disability is more related to motor symptoms that have a bad response to
medication such as swallowing and speech difficulties and gait and balance problems.[31] Finally
after ten years most people with the disease suffer autonomic disturbances, sleep problems,
mood alterations and cognitive decline.[31] All of them, but specially the latter, greatly increase
disability.[31][7]

The average life expectancy of a PD patient is lower than for people who do not have the
disease.[31] Mortality ratios are around twice of those unaffected.[31] Cognitive decline and
dementia, old age at onset, a more advanced disease, and presence of swallowing problems are
all mortality risk factors. Conversely a cause of death twice as common in PD patients than in the
healthy population is aspiration pneumonia.[31] On the other hand a disease mainly characterized
by tremor as opposed to rigidity predicts an improved survival.[31]
[edit] Epidemiology
Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is
the number of new cases per unit of person–time at risk (usually number of new cases per
thousand person–years); while prevalence is the total number of cases of the disease in the
population at a given time. PD is the most common neurodegenerative disorder after Alzheimer's
disease.[32] The prevalence is estimated at being 0.3 in the whole population in industrialized
countries, rising to 1% in those over 60 years of age and to 4% of the population over 80.[32]
Parkinson's disease might less prevalent in those of African and asian ancestry, although results
are controversial.[32] Some studies have also proposed that PD is more common in men than
women while others did not found any differences between the two groups.[32] Studies on
incidence report that it is between 8 and 18 per 100.000 person-years.[32]

[edit] Risk and protective factors

Many risk factors have been proposed in accordance to possible mechanisms of the disease.
However none have been conclusively related to PD. While many different epidemiological
studies have been carried out trying to prove or disprove the relationship between a given factor
and PD, they have commonly been biased, and results of different studies have been
contradictory.[6] Most replicated relationships are an increased risk of PD in those living in rural
environments and those exposed to pesticides; and a reduced risk in smokers.[6]

MPTP injections produce a range of symptoms similar to PD as well as a selective damage to the
dopamingergic neurons in the substantia nigra. This has led to theorizing that exposure to some
environmental toxins may increase the risk of suffering PD.[6] Toxins that have been consistently
related to the disease are certain pesticides and herbicides, with exposure doubling the risk of
having PD.[6] Conversely indirect measures of exposure to such toxins, such as living in rural
environments have also been found to increasing the risk of PD. Heavy metals exposure has also
been proposed to increase the risk of PD, being its hypothetical mechanism their accumulation in
the substantia nigra during the course of the disease, however studies on the issue have been
inconclusive.[6]

A protective effect of tobacco has been consistently found in epidemiological studies. The basis
for such effect is not known but possibilities include an effect of nicotine as dopamine stimulant.
[6]
Coffeine consumption has also been proposed to protect from PD, but the hypothesis requires
further validation.[6]
[edit] History

Frontespiece of Parkinson's classical essay on shaking palsy

The disease was not formally recognized and its symptoms were not documented until 1817 in
An Essay on the Shaking Palsy[33] by the British apothecary James Parkinson. Parkinson's disease
was then known as paralysis agitans (shaking palsy in English), the term "Parkinson's disease"
being coined later by Jean-Martin Charcot.[34]

[edit] Early descriptions

There are some early sources which talk about symptoms that are coherent with PD.[35] An
Egyptian papyrus from the 12th century B.C talks about a king drooling with age and the Bible
has references to tremor.[34][35] An early ayurvedic medical treatise dating back to the 10th century
B.C describes a disease that evolves with tremor, lack of movement, drooling and other
symptoms of PD. Moreover, this disease was treated with remedies derived from the mucuna
family, which is rich in L-DOPA.[35] Galen writes on a disease which most surely is PD when he
describes tremors that occur only at rest, postural changes and paralysis.[35]

After Galen there are no references known to be related to PD until the 17th century.[35] In this
and the following century different authors write about some of the elements of the disease,
precceding the description by Parkinson. Franciscus Sylvius separated as Galen tremor at rest
from other tremors, and Johannes Baptiste Sagar and Hieronymus David Gaubius talk about
festination.[35][36] John Hunter provided an excellent description of the disease, and it is even
thought that gave Parkinson the idea of collecting and describing patients with "paralisis
agitans".[35][37] Finally, Auguste François Chomel in his pathology treatise, which is contemporary
to Parkinson's essay, has many descriptions on abnormal movements and rigidity typical of PD.
[35]
[edit] XIXth century

In 1817 James Parkinson, aged 62, publishes his essay on the disease, reporting 6 cases of
paralysis agitans.[34] In "An Essay of the Shaking Palsy" he describes the patients' resting tremor,
abnormal posture and gait, paralysis and diminished muscle strength.[38] The accuracy of the
description of the disease course is also remarkable.[34] He also acknowledges the contributions
of many of the previous authors to the understanding of PD.[34] Although the article has been later
considered the first seminal work on the disease, it received very little attention for more than
forty years.[38] Nevertheless early neurologists who made further additions to the knowledge of
the disease include Trousseau, Charcot, Gowers, Kinnier Wilson and Erb.[34] Moreover Charcot
studies between 1868 and 1881 were a landmark in the understanding of the disease.[34] Among
other advances he made the distinction between rigidity, weakness and bradykinesia.[34] He also
led the disease to be re-named in behalf of James Parkinson.[34]

[edit] XXth century

First speculations of the anatomical substrate of PD were made 80 years after Parkinson's essay,
when Brissaud proposed that the disease had its origin in the subthalamus or the cerebral
peduncle and might be caused by an ischemic lesion.[34] In 1912 Frederic Lewy described a
pathologic finding in affected brains, later named "Lewy bodies".[34] It was Konstantin Tretiakoff
who in 1919 discovered that the substantia nigra was the main cerebral structure affected, but it
was not widely accepted until further studies by Hassler in 1938.[34] 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 his role on PD. He later won a Nobel Prize for his work.[39]

While levodopa was first synthesized in 1911 by Funk, it received little attention until the mid
20th century.[39] It entered clinical practice in 1967, and the first large study reporting
improvements in patients with Parkinson's disease resulting from treatment with levodopa was
published in 1968. Levodopa use was a major revolution in the management of PD which still
lasts.[39][40] Surgery for tremor was initiated in 1939 and was improved for over 20 years, but the
arrival of levodopa reduced its use dramatically.[41] By the late 1980s deep brain stimulation
emerged as a possible treatment and it was approved by the FDA in 1997.[42]
[edit] Research directions
[edit] Animal models

The tragedy of a group of drug addicts in California in the early 1980s who consumed a
contaminated and illicitly produced batch of the synthetic opiate MPPP brought to light MPTP as
a cause of PD symptoms.[43] This made it possible to develop the first animal model for
Parkinson's disease. The book The Case of the Frozen Addicts by William Langston documents
this tragedy and describes the first attempts at fetal brain tissue transplants to treat PD.

Other predominant toxin-based models employ the insecticide rotenone, the herbicide paraquat
and the fungicide maneb.[44] Models based on toxins are most commonly used in primates.
Transgenic rodent models also exist.[45]

[edit] Gene therapy

Gene therapy is currently under investigation.[7][46] It 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 which
helps to manage PD symptoms or protects the brain from further damage.[7] As of 2010 there are
four clinical trials using gene therapy in PD.[7] There have not been important adverse effects in
these trials although the clinical usefulness of gene therapy is still unknown.[7]

[edit] Neuroprotective treatments

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

Investigations on neuroprotection are at the forefront of PD research. Several molecules have

been proposed as potential treatments.[7] However none of them has been conclusively
demonstrated to reduce degeneration in clinical trials.[7] Agents currently under investigation as
neuroprotective agents include anti-apoptotic drugs (TCH346, CEP-1347), antiglutamatergic
agents, monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrial drugs (coenzyme
Q10, creatine), calcium channel blockers (isradipine) and growth factors (GDNF).[7]
[edit] Neural transplantation

Cell transplants in PD started around 1980 using very different tissues such as fetal, porcine,
carotid or retinal.[7] Although there was initial evidence of mesencephalic dopamine-producing
cell transplants being beneficial, the best constructed studies up to date indicate that cell
transplants have no effect.[7] An additional significant problem was the excess release of
dopamine by the transplanted tissue, leading to dystonias.[47] Stem cells transplants have raised
great recent interest. When transplanted into the brains of rodents and monkeys they survive and
improve behavioral abnormalities.[7][48] Nevertheless while fetal stem cells are the easiest to
manipulate their use is controversial.[7] Such controversy may be overcome with the use of
induced pluripotent stem cells from adults.[7]