Parkinson's disease
Overview
Parkinson's disease is a degenerative
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...

 disorder of the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

. The motor symptoms of Parkinson's disease result from the death of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

-generating cells in the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...

, 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
Motor skill
A motor skill is a learned sequence of movements that combine to produce a smooth, efficient action in order to master a particular task. The development of motor skill occurs in the motor cortex, the region of the cerebral cortex that controls voluntary muscle groups.- Development of motor skills...

, including shaking
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...

, rigidity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...

, slowness of movement and difficulty with walking and gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...

. Later, cognitive
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...

 and behavioural problems may arise, with dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

 commonly occurring in the advanced stages of the disease.
Encyclopedia
Parkinson's disease is a degenerative
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...

 disorder of the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

. The motor symptoms of Parkinson's disease result from the death of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

-generating cells in the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...

, 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
Motor skill
A motor skill is a learned sequence of movements that combine to produce a smooth, efficient action in order to master a particular task. The development of motor skill occurs in the motor cortex, the region of the cerebral cortex that controls voluntary muscle groups.- Development of motor skills...

, including shaking
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...

, rigidity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...

, slowness of movement and difficulty with walking and gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...

. Later, cognitive
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...

 and behavioural problems may arise, with dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

 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
Parkinsonism
Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...

, or a "parkinsonian syndrome". Parkinson's disease is often defined as a parkinsonian syndrome that is idiopathic
Idiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...

 (having no known cause), although some atypical cases have a genetic
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....

 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
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....

 of the disease is characterized by the accumulation of a protein called alpha-synuclein
Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the...

 into inclusions
Inclusion bodies
Inclusion bodies are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins...

 called Lewy bodies in neurons, and from insufficient formation and activity of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 produced in certain neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

s within parts of the midbrain. Lewy bodies are the pathological hallmark of the idiopathic disorder and the distrubution of the Lewy bodies throughout the Parkinsonian brain varies from one individual to another. The anatomical distribution of the Lewy body is often directily related to the expression and degree of the clinical symptoms of each individual. Diagnosis of typical cases is mainly based on symptoms, with tests such as neuroimaging
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...

 being used for confirmation.

Modern treatments are effective at managing the early motor symptoms of the disease, mainly through the use of levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...

 and dopamine agonist
Dopamine agonist
A dopamine agonist is a compound that activates dopamine receptors in the absence of dopamine. Dopamine agonists activate signaling pathways through the dopamine receptor and trimeric G-proteins, ultimately leading to changes in gene transcription.-Uses:...

s. 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
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...

, marked by involuntary writhing movements. Diet and some forms of rehabilitation have shown some effectiveness at alleviating symptoms. Surgery and deep brain stimulation
Deep brain stimulation
Deep brain stimulation is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain...

 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 model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...

s of the disease and investigations of the potential usefulness of gene therapy, stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...

 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
James Parkinson
James Parkinson was an English apothecary surgeon, geologist, paleontologist, and political activist. He is most famous for his 1817 work, An Essay on the Shaking Palsy in which he was the first to describe "paralysis agitans", a condition that would later be renamed Parkinson's disease by...

, 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
Michael J. Fox
Michael J. Fox, OC is a Canadian American actor, author, producer, activist and voice-over artist. With a film and television career spanning from the late 1970s, Fox's roles have included Marty McFly from the Back to the Future trilogy ; Alex P...

 and Muhammad Ali
Muhammad Ali
Muhammad Ali is an American former professional boxer, philanthropist and social activist...

.

Classification

The term parkinsonism
Parkinsonism
Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...

 is used for a motor syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...

 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
Idiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...

, secondary or acquired, hereditary parkinsonism, and parkinson plus syndrome
Parkinson plus syndrome
Parkinson-plus syndromes, also known as disorders of multiple system degeneration, are a group of neurodegenerative diseases featuring the classical features of Parkinson's disease with additional features that distinguish them from simple idiopathic Parkinson's disease...

s or multiple system degeneration. Parkinson's disease is the most common form of parkinsonism and is usually defined as "primary" parkinsonism, meaning parkinsonism with no external identifiable cause. 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.

PD is usually classified as a movement disorder
Movement disorder
Movement disorders include:* Akathisia * Akinesia * Associated Movements * Athetosis...

, although it also gives rise to several non-motor types of symptoms such as sensory deficits, cognitive difficulties or sleep problems. Parkinson plus diseases
Parkinson plus syndrome
Parkinson-plus syndromes, also known as disorders of multiple system degeneration, are a group of neurodegenerative diseases featuring the classical features of Parkinson's disease with additional features that distinguish them from simple idiopathic Parkinson's disease...

 are primary parkinsonisms which present additional features. They include multiple system atrophy
Multiple system atrophy
Multiple system atrophy is a degenerative neurological disorder. MSA is associated with the degeneration of nerve cells in specific areas of the brain. This cell degeneration causes problems with movement, balance and other autonomic functions of the body such as bladder control or blood pressure...

, progressive supranuclear palsy
Progressive supranuclear palsy
Progressive supranuclear palsy is a degenerative disease involving the gradual deterioration and death of specific areas of the brain....

, corticobasal degeneration
Corticobasal degeneration
Corticobasal degeneration or Corticobasal Ganglionic Degeneration is a rare progressive neurodegenerative disease involving the cerebral cortex and the basal ganglia. It is characterized by marked disorders in movement and cognitive dysfunction...

 and dementia with Lewy bodies
Dementia with Lewy bodies
Dementia with Lewy bodies , also known under a variety of other names including Lewy body dementia, diffuse Lewy body disease, cortical Lewy body disease, and senile dementia of Lewy type, is a type of dementia closely allied to both Alzheimers and Parkinson's Diseases...

.

In terms of pathophysiology
Pathophysiology
Pathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...

, PD is considered a synuclein
Synuclein
Synucleins are a family of soluble proteins common to vertebrates, primarily expressed in neural tissue and in certain tumors.- Family members :The synuclein family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein...

opathy due to an abnormal accumulation of alpha-synuclein
Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the...

 protein in the brain in the form of Lewy bodies
Lewy body
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in Parkinson's disease , Lewy Body Dementia and some other disorders. They are identified under the microscope when histology is performed on the brain....

, as opposed to other diseases such as Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

 where the brain accumulates tau protein
Tau protein
Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...

 in the form of neurofibrillary tangle
Neurofibrillary tangle
Neurofibrillary Tangles are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary marker of Alzheimer's Disease. Their presence is also found in numerous other diseases known as Tauopathies...

s. Nevertheless, there is clinical and pathological overlap between tauopathies
Tauopathy
Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in the human brain.The best known of these illnesses is Alzheimer's disease , where tau protein is deposited within neurons in the form of neurofibrillary tangles...

 and synucleinopathies. The most typical symptom of Alzheimer's disease, dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

, occurs in advanced stages of PD, while it is common to find neurofibrillary tangles in brains affected by PD.

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. They may represent parts of a continuum or they may be separate diseases.

Signs and symptoms

Parkinson's disease affects movement, producing motor symptoms. Non-motor symptoms, which include autonomic dysfunction
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...

, neuropsychiatric
Neuropsychiatry
Neuropsychiatry is the branch of medicine dealing with mental disorders attributable to diseases of the nervous system. It preceded the current disciplines of psychiatry and neurology, in as much as psychiatrists and neurologists had a common training....

 problems (mood, cognition, behavior or thought alterations), and sensory and sleep difficulties, are also common.

Motor

Four motor symptoms are considered cardinal
Cardinal sign (pathology)
In pathology, a cardinal sign or cardinal symptom is the primary or major clinical sign symptom by which a diagnosis is made.Often, there is a cluster of signs or symptoms that, taken together, are pathognomonic for a specific disease or syndrome....

 in PD: tremor, rigidity, slowness of movement, and postural instability.

Tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...

 is the most apparent and well-known symptom. 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. It is usually a rest tremor: maximal when the limb is at rest and disappearing with voluntary movement and sleep. 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. Frequency of PD tremor is between 4 and 6 hertz
Hertz
The hertz is the SI unit of frequency defined as the number of cycles per second of a periodic phenomenon. One of its most common uses is the description of the sine wave, particularly those used in radio and audio applications....

 (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. The term derives from the similarity between the movement in PD patients and the earlier pharmaceutical technique of manually making pills.

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. Performance of sequential and simultaneous movement is hindered. Bradykinesia is the most disabling symptom in the early stages of the disease. Initial manifestations are problems when performing daily tasks which require fine motor control such as writing, sewing or getting dressed. Clinical evaluation is based in similar tasks such as alternating movements between both hands or both feet. 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. Generally patients have less difficulty when some sort of external cue is provided.

Rigidity
Hypokinesia
Hypokinesia refers to decreased bodily movement. It is associated with basal ganglia diseases , mental health disorders and prolonged inactivity due to illness, amongst other diseases.Hypokinesia describes a spectrum of disorders:...

 is stiffness and resistance to limb movement caused by increased muscle tone
Muscle tone
In physiology, medicine, and anatomy, muscle tone is the continuous and passive partial contraction of the muscles, or the muscle’s resistance to passive stretch during resting state. It helps maintain posture, and it declines during REM sleep.-Purpose:Unconscious nerve impulses maintain the...

, an excessive and continuous contraction of muscles. In parkinsonism the rigidity can be uniform (lead-pipe rigidity) or ratchety (cogwheel rigidity). The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity. Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease. 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. 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
Balance disorder
A balance disorder is a disturbance that causes an individual to feel unsteady, for example when standing or walking. It may be accompanied by feelings of giddiness or wooziness, or having a sensation of movement, spinning, or floating...

 and frequent falls, and secondarily to bone fractures. Instability is often absent in the initial stages, especially in younger people. 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.

Other recognized motor signs and symptoms include gait and posture disturbances such as festination
Parkinsonian gait
Parkinsonian gait is the type of gait exhibited by patients suffering from Parkinson's disease . This disorder is caused by a deficiency of dopamine in the basal ganglia circuit leading to motor deficits...

 (rapid shuffling steps and a forward-flexed posture
Camptocormia
Camptocormia is a medical condition that is characterized by forward flexion of the spine, which is noticeable when standing or walking but disappears when lying down...

 when walking), speech and swallowing disturbances including voice disorders
Dysphonia
Dysphonia is the medical term for disorders of the voice: an impairment in the ability to produce voice sounds using the vocal organs . Thus, dysphonia is a phonation disorder...

, mask-like face expression
Hypomimia
Hypomimia, a medical sign, is a reduced degree of facial expression. It can be caused by motor impairment , as in Parkinson's disease, or by other causes, like psychological or psychiatric factors ....

 or small handwriting
Micrographia (handwriting)
Micrographia is a medical term used to describe abnormally small, cramped handwriting and/or the progression to continually smaller handwriting. This is one of the symptoms of Parkinson's disease...

, although the range of possible motor problems that can appear is large.

Neuropsychiatric

Parkinson's disease can cause neuropsychiatric
Neuropsychiatry
Neuropsychiatry is the branch of medicine dealing with mental disorders attributable to diseases of the nervous system. It preceded the current disciplines of psychiatry and neurology, in as much as psychiatrists and neurologists had a common training....

 disturbances which can range from mild to severe. This includes disorders of speech, cognition, mood, behaviour, and thought.

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. The most common cognitive deficit in affected individuals is executive dysfunction
Executive dysfunction
Executive dysfunction , in psychology , is a disruption to the efficacy of the executive system. It can refer to both neurocognitive deficits and behavioural symptoms...

, 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
Attention
Attention is the cognitive process of paying attention to one aspect of the environment while ignoring others. Attention is one of the most intensely studied topics within psychology and cognitive neuroscience....

 and slowed cognitive speed
Bradyphrenia
Bradyphrenia is a neurological term referring to the slowness of thought common to many disorders of the brain.-Diseases:Disorders characterized by bradyphrenia include Parkinson's disease and forms of schizophrenia...

 are among other cognitive difficulties. Memory is affected, specifically in recalling
Recall (memory)
Recall in memory refers to the retrieval of events or information from the past. Along with encoding and storage, it is one of the three core processes of memory. There are three main types of recall: free recall, cued recall and serial recall...

 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.

A person with PD has two to six times the risk of suffering dementia compared to the general population. The prevalence of dementia increases with duration of the disease. Dementia is associated with a reduced quality of life
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...

 in people with PD and their caregiver
Caregiver
Caregiver may refer to:* Caregiver or carer - an unpaid person who cares for someone requiring support due to a disability, frailty, mental health problem, learning disability or old age...

s, increased mortality, and a higher probability of needing nursing home care.

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
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...

, apathy
Apathy
Apathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...

 and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...

. Impulse control behaviors such as medication overuse and craving
Dopamine dysregulation syndrome
Dopamine dysregulation syndrome , sometimes known as hedonistic homeostatic dysregulation in Parkinson's disease, is a dysfunction of the reward system in subjects with Parkinson's disease due to a long exposure to dopamine replacement therapy...

, binge eating
Binge eating
Binge eating is a pattern of disordered eating which consists of episodes of uncontrollable eating. It is sometimes as a symptom of binge eating disorder. During such binges, a person rapidly consumes an excessive amount of food...

, hypersexuality
Hypersexuality
Hypersexuality is extremely frequent or suddenly increased sexual urges or sexual activity. Hypersexuality is typically associated with lowered sexual inhibitions. Although hypersexuality can be caused by some medical conditions or medications, in most cases the cause is unknown...

, or pathological gambling can appear in PD and have been related to the medications used to manage the disease. Psychotic
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...

 symptoms—hallucination
Hallucination
A hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...

s or delusion
Delusion
A delusion is a false belief held with absolute conviction despite superior evidence. Unlike hallucinations, delusions are always pathological...

s—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.

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. Symptoms can manifest in daytime drowsiness
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...

, disturbances in REM sleep, or insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...

. Alterations in the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...

 can lead to orthostatic hypotension
Orthostatic hypotension
Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...

 (low blood pressure upon standing), oily skin and excessive sweating, urinary incontinence
Urinary incontinence
Urinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...

 and altered sexual function. Constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...

 and gastric dysmotility can be severe enough to cause discomfort and even endanger health. PD is related to several eye and vision abnormalities such as decreased blink
Blink
Blinking is the rapid closing and opening of the eyelid. It is an essential function of the eye that helps spread tears across and remove irritants from the surface of the cornea and conjunctiva. Blink speed can be affected by elements such as fatigue, eye injury, medication, and disease...

 rate, dry eyes, deficient ocular pursuit (eye tracking) and saccadic movements
Saccade
A saccade is a fast movement of an eye, head or other part of an animal's body or device. It can also be a fast shift in frequency of an emitted signal or other quick change. Saccades are quick, simultaneous movements of both eyes in the same direction...

 (fast automatic movements of both eyes in the same direction), difficulties in directing gaze upward, and blurred
Blurred vision
-Causes:There are many causes of blurred vision:* Use of atropine or other anticholinergics* Presbyopia -- Difficulty focusing on objects that are close. The elderly are common victims....

 or double vision
Double vision
Double vision refers to diplopia, the perception of two images from a single object.Double vision may also refer to:- Music :* Double Vision * Double Vision...

. Changes in perception may include an impaired sense of smell
Olfaction
Olfaction is the sense of smell. This sense is mediated by specialized sensory cells of the nasal cavity of vertebrates, and, by analogy, sensory cells of the antennae of invertebrates...

, sensation of pain and paresthesia
Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...

 (skin tingling and numbness). All of these symptoms can occur years before diagnosis of the disease.

Causes

Most people with Parkinson's disease have idiopathic
Idiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...

 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. 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.

Mutations in specific genes have been conclusively shown to cause PD. These genes code for alpha-synuclein
Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the...

 (SNCA), parkin
Parkin (ligase)
Parkin is a protein which in humans is encoded by the PARK2 gene. The precise function of this protein is unknown; however, the protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for...

 (PRKN), leucine-rich repeat kinase 2 (LRRK2
LRRK2
Leucine-rich repeat kinase 2 , also known as dardarin, is an enzyme that in humans is encoded by the LRRK2 gene. LRRK2 is a member of the leucine-rich repeat kinase family...

 or dardarin), PTEN-induced putative kinase 1 (PINK1
PINK1
PTEN-induced putative kinase 1 is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene.-External links:* -Further reading:...

), DJ-1
PARK7
Parkinson disease 7, also known as PARK7, is a protein which in humans is encoded by the PARK7 gene. It is also known as DJ-1.- Function :...

 and ATP13A2
ATP13A2
Probable cation-transporting ATPase 13A2 is an enzyme that in humans is encoded by the ATP13A2 gene.-Further reading:...

. 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. The most extensively studied PD-related genes are SNCA and LRRK2. Mutations in genes including SNCA, LRRK2 and glucocerebrosidase
Glucocerebrosidase
β-Glucocerebrosidase is an enzyme with glucosylceramidase activity that is needed to cleave, by hydrolysis, the beta-glucosidic linkage of the chemical glucocerebroside, an intermediate in glycolipid metabolism...

 (GBA) have been found to be risk factors for sporadic PD. Mutations in GBA are known to cause Gaucher's disease
Gaucher's disease
Gaucher's disease is a genetic disease in which a fatty substance accumulates in cells and certain organs.Gaucher's disease is the most common of the lysosomal storage diseases. It is caused by a hereditary deficiency of the enzyme glucosylceramidase. The enzyme acts on the fatty acid...

. Genome-wide association studies
Genome-wide association study
In genetic epidemiology, a genome-wide association study , also known as whole genome association study , is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait...

, which search for mutated allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...

s with low penetrance in sporadic cases, have now yielded many positive results.

The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of Lewy bodies
Lewy body
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in Parkinson's disease , Lewy Body Dementia and some other disorders. They are identified under the microscope when histology is performed on the brain....

. Missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...

s of the gene (in which a single nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...

 is changed), and duplications
Gene duplication
Gene duplication is any duplication of a region of DNA that contains a gene; it may occur as an error in homologous recombination, a retrotransposition event, or duplication of an entire chromosome.The second copy of the gene is often free from selective pressure — that is, mutations of it have no...

 and triplications of the locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...

 containing it have been found in different groups with familial PD. Missense mutations are rare. On the other hand, multiplications of the SNCA locus account for around 2% of familial cases. Multiplications have been found in asymptomatic carrier
Asymptomatic carrier
An asymptomatic carrier is a person or other organism that has contracted an infectious disease, but who displays no symptoms. Although unaffected by the disease themselves, carriers can transmit it to others...

s, which indicate that penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...

 is incomplete or age-dependent.

The LRRK2 gene (PARK8) encodes for a protein called dardarin. The name dardarin was taken from a Basque
Basque language
Basque is the ancestral language of the Basque people, who inhabit the Basque Country, a region spanning an area in northeastern Spain and southwestern France. It is spoken by 25.7% of Basques in all territories...

 word for tremor, because this gene was first identified in families from England and the north of Spain. 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. There are many different mutations described in LRRK2, however unequivocal proof of causation only exists for a small number.

Pathology

Anatomical pathology

The basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...

, a group of "brain structures" innervated by the dopaminergic system, are the most seriously affected brain areas in PD. The main pathological
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....

 characteristic of PD is cell death in the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...

 and, more specifically, the ventral (front) part of the pars compacta
Pars compacta
-Anatomy:In humans, the nerve cell bodies of the pars compacta are coloured black by the pigment neuromelanin. The degree of pigmentation increases with age. This pigmentation is visible as a distinctive black stripe in brain sections and is the origin of the name given to this area. The neurons...

, affecting up to 70% of the cells by the time death occurs.

Macroscopic
Macroscopic
The macroscopic scale is the length scale on which objects or processes are of a size which is measurable and observable by the naked eye.When applied to phenomena and abstract objects, the macroscopic scale describes existence in the world as we perceive it, often in contrast to experiences or...

 alterations can be noticed on cut surfaces of the brainstem, where neuronal loss can be inferred from a reduction of melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...

 pigmentation in the substantia nigra and locus coeruleus. The histopathology
Histopathology
Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...

 (microscopic anatomy) of the substantia nigra and several other brain regions shows neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

al loss and Lewy bodies
Lewy body
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in Parkinson's disease , Lewy Body Dementia and some other disorders. They are identified under the microscope when histology is performed on the brain....

 in many of the remaining nerve cells. Neuronal loss is accompanied by death of astrocytes (star-shaped glial cells) and activation of the microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...

 (another type of glial cell). Lewy bodies are a key pathological feature of PD.

Pathophysiology

The primary symptoms of Parkinson's disease result from greatly reduced activity of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

-secreting cells caused by cell death in the pars compacta
Pars compacta
-Anatomy:In humans, the nerve cell bodies of the pars compacta are coloured black by the pigment neuromelanin. The degree of pigmentation increases with age. This pigmentation is visible as a distinctive black stripe in brain sections and is the origin of the name given to this area. The neurons...

 region of the substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...

.

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
Limbic system
The limbic system is a set of brain structures including the hippocampus, amygdala, anterior thalamic nuclei, septum, limbic cortex and fornix, which seemingly support a variety of functions including emotion, behavior, long term memory, and olfaction. The term "limbic" comes from the Latin...

 and orbitofrontal circuits, with names indicating the main projection area of each circuit. 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. Scientifically, the motor circuit has been examined the most intensively.

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. 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
Hypokinesia
Hypokinesia refers to decreased bodily movement. It is associated with basal ganglia diseases , mental health disorders and prolonged inactivity due to illness, amongst other diseases.Hypokinesia describes a spectrum of disorders:...

, an overall reduction in motor output. 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 dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...

s.

Brain cell death

There is speculation of several mechanisms by which the brain cells could be lost. One mechanism consists of an abnormal accumulation of the protein alpha-synuclein
Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the...

 bound to ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...

 in the damaged cells. This insoluble protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 accumulates inside neurones forming inclusions called Lewy bodies. According to the Braak staging
Braak staging
The Braak staging is a classification of Parkinson's disease based on pathological findings.The main pathological characteristic of PD 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 the time the patient dies....

, a classification of the disease based on pathological findings, Lewy bodies first appear in the olfactory bulb
Olfactory bulb
The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...

, medulla oblongata
Medulla oblongata
The medulla oblongata is the lower half of the brainstem. In discussions of neurology and similar contexts where no ambiguity will result, it is often referred to as simply the medulla...

 and pontine tegmentum
Pontine tegmentum
The pontine tegmentum is a part of the pons of the brain involved in the initiation of REM sleep. It includes the pedunculopontine nucleus and the laterodorsal tegmental nucleus, among others, and is located near the raphe nucleus and the locus ceruleus....

, 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
Neocortex
The neocortex , also called the neopallium and isocortex , is a part of the brain of mammals. It is the outer layer of the cerebral hemispheres, and made up of six layers, labelled I to VI...

. 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. 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
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

, are not common unless the person is demented.

Other cell-death mechanisms include proteosomal and lysosomal
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...

 system dysfunction and reduced mitochondrial activity. Iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. It may be related to oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...

, protein aggregation
Protein aggregation
Protein aggregation is the aggregation of mis-folded proteins, and is thought to be responsible for many degenerative diseases, such as Alzheimer's. It has also been implicated in CAG repeat diseases....

 and neuronal death, but the mechanisms are not fully understood.

Diagnosis

A physician will diagnose Parkinson's disease from the medical history
Medical history
The medical history or anamnesis of a patient is information gained by a physician by asking specific questions, either of the patient or of other people who know the person and can give suitable information , with the aim of obtaining information useful in formulating a diagnosis and providing...

 and a neurological examination
Neurological examination
A neurological examination is the assessment of sensory neuron and motor responses, especially reflexes, to determine whether the nervous system is impaired...

. 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
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...

 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.

Other causes that can secondarily produce a parkinsonian syndrome are Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

, multiple cerebral infarction
Cerebral infarction
A cerebral infarction is the ischemic kind of stroke due to a disturbance in the blood vessels supplying blood to the brain. It can be atherothrombotic or embolic. Stroke caused by cerebral infarction should be distinguished from two other kinds of stroke: cerebral hemorrhage and subarachnoid...

 and drug-induced parkinsonism. Parkinson plus syndrome
Parkinson plus syndrome
Parkinson-plus syndromes, also known as disorders of multiple system degeneration, are a group of neurodegenerative diseases featuring the classical features of Parkinson's disease with additional features that distinguish them from simple idiopathic Parkinson's disease...

s such as progressive supranuclear palsy
Progressive supranuclear palsy
Progressive supranuclear palsy is a degenerative disease involving the gradual deterioration and death of specific areas of the brain....

 and multiple system atrophy
Multiple system atrophy
Multiple system atrophy is a degenerative neurological disorder. MSA is associated with the degeneration of nerve cells in specific areas of the brain. This cell degeneration causes problems with movement, balance and other autonomic functions of the body such as bladder control or blood pressure...

 must be ruled out. Anti-Parkinson's medications are typically less effective at controlling symptoms in Parkinson plus syndromes. 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. 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.

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
National Institute of Neurological Disorders and Stroke
The National Institute of Neurological Disorders and Stroke is a part of the U.S. National Institutes of Health . It conducts and funds research on brain and nervous system disorders and has a budget of just over US$1.5 billion...

. 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 dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...

s induced by the intake of excessive levodopa. Accuracy of diagnostic criteria evaluated at autopsy is 75–90%, with specialists such as neurologists having the highest rates.

Computed tomography
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...

 (CT) and magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...

 (MRI) brain scans of people with PD usually appear normal. These techniques are nevertheless useful to rule out other diseases that can be secondary causes of parkinsonism, such as basal ganglia tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

s, vascular
Vascular
Vascular in zoology and medicine means "related to blood vessels", which are part of the circulatory system. An organ or tissue that is vascularized is heavily endowed with blood vessels and thus richly supplied with blood....

 pathology and hydrocephalus
Hydrocephalus
Hydrocephalus , also known as "water in the brain," is a medical condition in which there is an abnormal accumulation of cerebrospinal fluid in the ventricles, or cavities, of the brain. This may cause increased intracranial pressure inside the skull and progressive enlargement of the head,...

. A specific technique of MRI, diffusion MRI
Diffusion MRI
Diffusion MRI is a magnetic resonance imaging method that produces in vivo images of biological tissues weighted with the local microstructural characteristics of water diffusion, which is capable of showing connections between brain regions...

, has been reported to be useful at discriminating between typical and atypical parkinsonism, although its exact diagnostic value is still under investigation. Dopaminergic function in the basal ganglia can be measured with different PET
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...

 and SPECT
Single photon emission computed tomography
Single-photon emission computed tomography is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera. However, it is able to provide true 3D information...

 radiotracers. Examples are ioflupane (123I) (trade name DaTSCAN) and iometopane (Dopascan) for SPECT or fludeoxyglucose (18F) for PET. A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing PD.

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
Dopa decarboxylase inhibitor
An aromatic L-amino acid decarboxylase inhibitor is a drug which inhibits the synthesis of dopamine by the enzyme aromatic L-amino acid decarboxylase ....

 or COMT inhibitor
COMT inhibitor
A COMT inhibitor is a drug that inhibits the action of catechol-O-methyl transferase. This enzyme is involved in degrading neurotransmitters. COMT inhibitors are used in the treatment of Parkinson's disease....

), dopamine agonist
Dopamine agonist
A dopamine agonist is a compound that activates dopamine receptors in the absence of dopamine. Dopamine agonists activate signaling pathways through the dopamine receptor and trimeric G-proteins, ultimately leading to changes in gene transcription.-Uses:...

s and MAO-B inhibitors
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....

. 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. 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. 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. When medications are not enough to control symptoms, surgery and deep brain stimulation can be of use. In the final stages of the disease, palliative care
Palliative care
Palliative care is a specialized area of healthcare that focuses on relieving and preventing the suffering of patients...

 is provided to enhance quality of life.

Levodopa

Levodopa has been the most widely used treatment for over 30 years. L-DOPA is converted into dopamine in the dopaminergic neurons by dopa decarboxylase
Aromatic L-amino acid decarboxylase
Aromatic L-amino acid decarboxylase is a lyase enzyme.-Reactions:It catalyzes several different decarboxylation reactions:* L-DOPA to dopamine - a neurotransmitter* 5-HTP to serotonin - also a neurotransmitter...

. Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor symptoms.

Only 5–10% of L-DOPA crosses the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

. The remainder is often metabolized to dopamine elsewhere, causing a variety of side effects including nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...

s and joint stiffness. Carbidopa
Carbidopa
Carbidopa is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa.- Pharmacology :...

 and benserazide
Benserazide
Benserazide is a peripherally-acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood-brain barrier.- Indications :...

 are peripheral dopa decarboxylase inhibitor
Dopa decarboxylase inhibitor
An aromatic L-amino acid decarboxylase inhibitor is a drug which inhibits the synthesis of dopamine by the enzyme aromatic L-amino acid decarboxylase ....

s, which help to prevent the metabolism of L-DOPA before it reaches the dopaminergic neurons, therefore reducing side effects and increasing bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...

. They are generally given as combination preparations with levodopa. Existing preparations are carbidopa/levodopa
Carbidopa/levodopa
Carbidopa/levodopa is the combination of carbidopa and levodopa and is used to treat Parkinson's disease and dopamine-responsive dystonia . It is sold under several brand names, including Sinemet, Parcopa, and Atamet...

 (co-careldopa) and benserazide/levodopa
Benserazide
Benserazide is a peripherally-acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood-brain barrier.- Indications :...

 (co-beneldopa). Levodopa has been related to dopamine dysregulation syndrome
Dopamine dysregulation syndrome
Dopamine dysregulation syndrome , sometimes known as hedonistic homeostatic dysregulation in Parkinson's disease, is a dysfunction of the reward system in subjects with Parkinson's disease due to a long exposure to dopamine replacement therapy...

, which is a compulsive overuse of the medication, and punding. There are controlled release
Slow-release
Slow-release is a strategy in material science in which a chemical compound is introduced into a system at a reduced speed. Slow-release is applied in fertilizers, pesticides and drugs....

 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.

Tolcapone
Tolcapone
Tolcapone is a drug that inhibits the enzyme catechol-O-methyl transferase . - Uses :Tolcapone is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa medication.- Chemistry :...

 inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of levodopa. It has been used to complement levodopa; however, its usefulness is limited by possible side effects such as liver damage. A similarly effective drug, entacapone
Entacapone
Entacapone is a drug that functions as a catechol-O-methyl transferase inhibitor. It is used in the treatment of Parkinson's disease....

, has not been shown to cause significant alterations of liver function. Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.

Levodopa preparations lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...

s and fluctuations in the response to medication. 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). For this reason, levodopa doses are kept as low as possible while maintaining functionality. Delaying the initiation of therapy with levodopa by using alternatives (dopamine agonists and MAO-B inhibitors) is common practice. 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
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...

. Most people with PD will eventually need levodopa and later develop motor side effects.

Dopamine agonists

Several dopamine agonist
Dopamine agonist
A dopamine agonist is a compound that activates dopamine receptors in the absence of dopamine. Dopamine agonists activate signaling pathways through the dopamine receptor and trimeric G-proteins, ultimately leading to changes in gene transcription.-Uses:...

s that bind to dopaminergic post-synaptic receptors in the brain have similar effects to levodopa. 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. When used in late PD they are useful at reducing the off periods. Dopamine agonists include bromocriptine
Bromocriptine
Bromocriptine , an ergoline derivative, is a dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease , hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes.- Indications :Amenorrhea, female infertility, galactorrhea, hypogonadism, and acromegaly...

, pergolide
Pergolide
Pergolide is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease....

, pramipexole
Pramipexole
Pramipexole is a non-ergoline dopamine agonist indicated for treating early-stage Parkinson's disease and restless legs syndrome...

, ropinirole
Ropinirole
Ropinirole is a non-ergoline dopamine agonist. It is manufactured by GlaxoSmithKline , Cipla and Sun Pharmaceutical. It is used in the treatment of Parkinson's disease...

, piribedil
Piribedil
Piribedil is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist...

, cabergoline
Cabergoline
Cabergoline , an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. In vitro, rat studies show cabergoline has a direct inhibitory effect on pituitary lactotroph cells...

, apomorphine
Apomorphine
Apomorphine is a non-selective dopamine agonist which activates both D1-like and D2-like receptors, with some preference for the latter subtypes. It is historically a morphine decomposition product by boiling with concentrated acid, hence the -morphine suffix...

 and lisuride
Lisuride
Lisuride is an antiparkinson agent of the iso-ergoline class, chemically related to the dopaminergic ergoline Parkinson's drugs. Lisuride is described as free base and as hydrogen maleate salt.Lisuride is used to lower prolactin and, in low doses, to prevent migraine attacks...

.

Dopamine agonists produce significant, although usually mild, side effects including drowsiness
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...

, hallucinations, insomnia, nausea and constipation. Sometimes side effects appear even at a minimal clinically effective dose, leading the physician to search for a different drug. Compared with levodopa, dopamine agonists may delay motor complications of medication use but are less effective at controlling symptoms. Nevertheless, they are usually effective enough to manage symptoms in the initial years. They tend to be more expensive than levodopa. 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. Thus dopamine agonists are the preferred initial treatment for earlier onset, as opposed to levodopa in later onset. 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.

Apomorphine
Apomorphine
Apomorphine is a non-selective dopamine agonist which activates both D1-like and D2-like receptors, with some preference for the latter subtypes. It is historically a morphine decomposition product by boiling with concentrated acid, hence the -morphine suffix...

, a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD. It is administered by intermittent injections or continuous subcutaneous infusions. Since secondary effects such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be closely monitored. Two dopamine agonists that are administered through skin patches (lisuride
Lisuride
Lisuride is an antiparkinson agent of the iso-ergoline class, chemically related to the dopaminergic ergoline Parkinson's drugs. Lisuride is described as free base and as hydrogen maleate salt.Lisuride is used to lower prolactin and, in low doses, to prevent migraine attacks...

 and rotigotine
Rotigotine
Rotigotine is a non-ergoline dopamine agonist indicated for the treatment of Parkinson's disease and restless legs syndrome in Europe and the United States...

) 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.

MAO-B inhibitors

MAO-B inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....

s (selegiline
Selegiline
Selegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A...

 and rasagiline
Rasagiline
Rasagiline is an irreversible inhibitor of monoamine oxidase used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. It is selective for MAO type B over type A by a factor of fourteen....

) 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
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...

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

Other drugs

Other drugs such as amantadine
Amantadine
Amantadine is the organic compound known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral and an...

 and anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....

s may be useful as treatment of motor symptoms. However, the evidence supporting them lacks quality, so they are not first choice treatments. 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. Examples are the use of clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...

 for psychosis, cholinesterase inhibitors for dementia, and modafinil
Modafinil
Modafinil is an analeptic drug manufactured by Cephalon, and is approved by the U.S. Food and Drug Administration for the treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea...

 for daytime sleepiness
Excessive daytime sleepiness
Excessive daytime sleepiness is characterized by persistent sleepiness, and often a general lack of energy, even after apparently adequate night time sleep...

. A 2010 meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...

 found that non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...

s (apart from acetaminophen and aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

), 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.

Surgery and deep brain stimulation

Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa, the number of operations declined. 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. Surgery for PD can be divided in two main groups: lesional and deep brain stimulation
Deep brain stimulation
Deep brain stimulation is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain...

 (DBS). Target areas for DBS or lesions include the thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...

, the globus pallidus
Globus pallidus
The globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...

  or the subthalamic nucleus
Subthalamic nucleus
The subthalamic nucleus is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. Anatomically, it is the major part of subthalamus. As suggested by its name, the subthalamic nucleus is located ventral to the thalamus. It is also...

. Deep brain stimulation
Deep brain stimulation
Deep brain stimulation is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain...

 (DBS) is the most commonly used surgical treatment. It involves the implantation of a medical device called a brain pacemaker
Brain pacemaker
"Brain pacemakers" are used to treat people who suffer from epilepsy, Parkinson's disease, major depression and other diseases. The pacemaker is a medical device that is implanted into the brain to send electrical signals into the tissue. Depending on the area of the brain that is targeted, the...

, 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. Other, less common, surgical therapies involve the formation of lesions in specific subcortical areas (a technique known as pallidotomy
Pallidotomy
Pallidotomy is a procedure where a tiny electrical probe is placed in the globus pallidus , which is then heated to 80 degrees celsius for 60 seconds, to destroy a small area of brain cells...

 in the case of the lesion being produced in the globus pallidus).

Rehabilitation

There is some evidence that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality. Regular physical exercise
Physical exercise
Physical exercise is any bodily activity that enhances or maintains physical fitness and overall health and wellness. It is performed for various reasons including strengthening muscles and the cardiovascular system, honing athletic skills, weight loss or maintenance, as well as for the purpose of...

 with or without physiotherapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life. 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. In terms of improving flexibility and range of motion for patients experiencing rigidity
Rigidity
Rigid or rigidity may refer to:*Stiffness, the property of a solid body to resist deformation, which is sometimes referred to as rigidity*Structural rigidity, a mathematical theory of the stiffness of ensembles of rigid objects connected by hinges...

, 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
Diaphragmatic breathing
Diaphragmatic breathing, abdominal breathing, belly breathing or deep breathing is breathing that is done by contracting the diaphragm, a muscle located horizontally between the chest cavity and stomach cavity...

, and meditation
Meditation
Meditation is any form of a family of practices in which practitioners train their minds or self-induce a mode of consciousness to realize some benefit....

 techniques. As for gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...

 and addressing the challenges associated with the disease such as hypokinesia
Hypokinesia
Hypokinesia refers to decreased bodily movement. It is associated with basal ganglia diseases , mental health disorders and prolonged inactivity due to illness, amongst other diseases.Hypokinesia describes a spectrum of disorders:...

 (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
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...

 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). 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. 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. Exercise may improve constipation.

One of the most widely practiced treatments for speech disorders associated with Parkinson's disease is the Lee Silverman voice treatment
Lee Silverman voice treatment
The Lee Silverman voice treatment is one of the most widely practiced treatment for speech disorders associated with Parkinson's disease . It focuses on increasing vocal loudness and has an intensive approach of one month. Speech therapy and specifically LSVT may improve voice and speech function...

 (LSVT). Speech therapy and specifically LSVT may improve speech. Occupational therapy
Occupational therapy
Occupational therapy is a discipline that aims to promote health by enabling people to perform meaningful and purposeful activities. Occupational therapists work with individuals who suffer from a mentally, physically, developmentally, and/or emotionally disabling condition by utilizing treatments...

 (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. 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.

Diet

Muscles and nerves that control the digestive process may be affected by PD, resulting in constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...

 and gastroparesis
Gastroparesis
Gastroparesis, also called delayed gastric emptying, is a medical condition consisting of a paresis of the stomach, resulting in food remaining in the stomach for a longer period of time than normal. Normally, the stomach contracts to move food down into the small intestine for digestion. The...

 (food remaining in the stomach for a longer period of time than normal). 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. As the disease advances, swallowing difficulties (dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....

) may appear. In such cases it may be helpful to use thickening agent
Thickening agent
Thickening agents, or thickeners, is the term applied to substances which increase the viscosity of a solution or liquid/solid mixture without substantially modifying its other properties; although most frequently applied to foods where the target property is taste, the term also is applicable to...

s for liquid intake and an upright posture when eating, both measures reducing the risk of choking. Gastrostomy
Gastrostomy
Gastrostomy refers to a surgical opening into the stomach. Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression....

 to deliver food directly into the stomach is possible in severe cases.

Levodopa and protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s use the same transportation system in the intestine and the blood-brain barrier, thereby competing for access. When they are taken together, this results in a reduced effectiveness of the drug. Therefore, when levodopa is introduced, excessive protein consumption is discouraged and well balanced Mediterranean diet
Mediterranean diet
The Mediterranean diet is a modern nutritional recommendation inspired by the traditional dietary patterns of southern Italy, Crete and much of the rest of Greece in the 1960s....

 is recommended. In advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons. To minimize interaction with proteins, levodopa should be taken 30 minutes before meals. At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.

Palliative care

Palliative care
Palliative care
Palliative care is a specialized area of healthcare that focuses on relieving and preventing the suffering of patients...

 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
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...

 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.

Other treatments

Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias. Its usefulness in PD is an open research topic, although recent studies have shown no effect by rTMS. Several nutrient
Nutrient
A nutrient is a chemical that an organism needs to live and grow or a substance used in an organism's metabolism which must be taken in from its environment. They are used to build and repair tissues, regulate body processes and are converted to and used as energy...

s have been proposed as possible treatments; however there is no evidence that vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...

s or food additive
Food additive
Food additives are substances added to food to preserve flavor or enhance its taste and appearance.Some additives have been used for centuries; for example, preserving food by pickling , salting, as with bacon, preserving sweets or using sulfur dioxide as in some wines...

s improve symptoms. There is no evidence to substantiate that acupuncture
Acupuncture
Acupuncture is a type of alternative medicine that treats patients by insertion and manipulation of solid, generally thin needles in the body....

 and practice of Qigong
Qigong
Qigong or chi kung is a practice of aligning breath, movement, and awareness for exercise, healing, and meditation...

, 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. 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, their intake is not free of risks. Life-threatening adverse reactions have been described, such as the neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...

.

Prognosis

PD invariably progresses with time. The Hoehn and Yahr scale
Hoehn and Yahr scale
The Hoehn and Yahr scale is a commonly used system for describing how the symptoms of Parkinson's disease progress. It was originally published in 1967 in the journal Neurology by Melvin Yahr and Margaret Hoehn. The original scale included stages 1 through 5. Since then, stage 0 has been added, and...

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

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

The life expectancy
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...

 of people with PD is reduced. Mortality ratios
Standardized mortality ratio
The standardized mortality ratio or SMR in epidemiology is the ratio of observed deaths to expected deaths, where expected deaths are calculated for a typical area with the same age and gender mix by looking at the death rates for different ages and genders in the larger population.The SMR may be...

 are around twice those of unaffected people. Cognitive decline and dementia, old age at onset, a more advanced disease state and presence of swallowing problems are all mortality risk factor
Risk factor
In epidemiology, a risk factor is a variable associated with an increased risk of disease or infection. Sometimes, determinant is also used, being a variable associated with either increased or decreased risk.-Correlation vs causation:...

s. On the other hand a disease pattern mainly characterized by tremor as opposed to rigidity predicts an improved survival. Death from aspiration pneumonia
Aspiration pneumonia
Aspiration pneumonia is bronchopneumonia that develops due to the entrance of foreign materials into the bronchial tree, usually oral or gastric contents...

 is twice as common in individuals with PD as in the healthy population.

Epidemiology

PD is the second most common neurodegenerative disorder
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...

 after Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

. The prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...

 (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. 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. PD may be less prevalent in those of African and Asian ancestry, although this finding is disputed. Some studies have proposed that it is more common in men than women, but others failed to detect any differences between the two sexes. The incidence
Incidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...

 of PD is between 8 and 18 per 100,000 person–years.

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

Risk factors

Injections of the synthetic neurotoxin MPTP
MPTP
MPTP is a neurotoxin precursor to MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain...

 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. Exposure to toxins that have been consistently related to the disease can double the risk of PD, and include certain pesticide
Pesticide
Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...

s, such as rotenone
Rotenone
Rotenone is an odorless chemical that is used as a broad-spectrum insecticide, piscicide, and pesticide. It occurs naturally in the roots and stems of several plants such as the jicama vine plant...

 or paraquat
Paraquat
Paraquat is the trade name for N,N′-dimethyl-4,4′-bipyridinium dichloride, one of the most widely used herbicides in the world. Paraquat, a viologen, is quick-acting and non-selective, killing green plant tissue on contact. It is also toxic to human beings and animals...

, and herbicide
Herbicide
Herbicides, also commonly known as weedkillers, are pesticides used to kill unwanted plants. Selective herbicides kill specific targets while leaving the desired crop relatively unharmed. Some of these act by interfering with the growth of the weed and are often synthetic "imitations" of plant...

s, such as Agent Orange
Agent Orange
Agent Orange is the code name for one of the herbicides and defoliants used by the U.S. military as part of its herbicidal warfare program, Operation Ranch Hand, during the Vietnam War from 1961 to 1971. Vietnam estimates 400,000 people were killed or maimed, and 500,000 children born with birth...

. Indirect measures of exposure, such as living in rural environments, have been found to increase the risk of PD. 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.

Protective factors

Caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...

 consumption protects against PD. "Prospective epidemiologic studies performed in large cohorts of men (total: 374,003 subjects) agree in which the risk of suffering Parkinson's disease diminishes progressively as the consumption of coffee and other caffeinated beverages increases." Although tobacco smoking is devastating for longevity or quality of life, it 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. The basis for this effect is not known, but possibilities include an effect of nicotine
Nicotine
Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...

 as a dopamine stimulant. Tobacco smoke contains compounds that act as MAO inhibitors that also might contribute to this effect. Antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

s, 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. The results regarding fat and fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...

s have been contradictory, with various studies reporting protective effects, risk-enhancing effects or no effects. Finally there have been preliminary indications of a possible protective role of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...

s and anti-inflammatory
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...

 drugs.

History

Several early sources, including an Egyptian
Ancient Egypt
Ancient Egypt was an ancient civilization of Northeastern Africa, concentrated along the lower reaches of the Nile River in what is now the modern country of Egypt. Egyptian civilization coalesced around 3150 BC with the political unification of Upper and Lower Egypt under the first pharaoh...

 papyrus
Papyrus
Papyrus is a thick paper-like material produced from the pith of the papyrus plant, Cyperus papyrus, a wetland sedge that was once abundant in the Nile Delta of Egypt....

, an Ayurvedic
Ayurveda
Ayurveda or ayurvedic medicine is a system of traditional medicine native to India and a form of alternative medicine. In Sanskrit, words , meaning "longevity", and , meaning "knowledge" or "science". The earliest literature on Indian medical practice appeared during the Vedic period in India,...

 medical treatise, the Bible
Bible
The Bible refers to any one of the collections of the primary religious texts of Judaism and Christianity. There is no common version of the Bible, as the individual books , their contents and their order vary among denominations...

, or Galen
Galen
Aelius Galenus or Claudius Galenus , better known as Galen of Pergamon , was a prominent Roman physician, surgeon and philosopher...

's writings, describe symptoms resembling those of PD. After Galen there are no references unambiguously related to PD until the 17th century. In the 17th and 18th centuries, several authors wrote about elements of the disease, including Sylvius
Franciscus Sylvius
Franciscus Sylvius , born Franz de le Boë, was a Dutch physician and scientist who was an early champion of Descartes', Van Helmont's and William Harvey's work and theories...

, Gaubius
Hieronymus David Gaubius
Hieronymus David Gaubius was a German physician and chemist.-Life:He was a native of Heidelberg. He studied medicine and sciences at the Universities of Harderwijk and Leiden, where he was a pupil of Hermann Boerhaave and Bernhard Siegfried Albinus...

, Hunter
John Hunter (surgeon)
John Hunter FRS was a Scottish surgeon regarded as one of the most distinguished scientists and surgeons of his day. He was an early advocate of careful observation and scientific method in medicine. The Hunterian Society of London was named in his honour...

 and Chomel
Auguste François Chomel
Auguste François Chomel was a French pathologist who was born in Paris. He was a professor at the Hôpital de la Charité in Paris, and in 1827 succeeded René Laënnec as chair of clinical medicine of the Faculté de Paris.Chomel was an important member of the pathological anatomy movement of early...

.

In 1817 an English doctor, James Parkinson
James Parkinson
James Parkinson was an English apothecary surgeon, geologist, paleontologist, and political activist. He is most famous for his 1817 work, An Essay on the Shaking Palsy in which he was the first to describe "paralysis agitans", a condition that would later be renamed Parkinson's disease by...

, published his essay reporting six cases of paralysis agitans. 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. Early neurologists who made further additions to the knowledge of the disease include Trousseau
Armand Trousseau
Armand Trousseau was a French internist. His contributions to medicine include Trousseau sign of malignancy, Trousseau sign of latent tetany, Trousseau-Lallemand bodies , and the truism, "use new drugs quickly, while they still work."-Biography:A native of Tours, Indre-et-Loire, Armand Trousseau...

, Gowers
William Richard Gowers
Sir William Richard Gowers was a British neurologist.The Gowers' tract is named after him....

, Kinnier Wilson
Samuel Alexander Kinnier Wilson
Samuel Alexander Kinnier Wilson was a British neurologist who was the first to describe Wilson's disease.-Biography:...

 and Erb
Wilhelm Heinrich Erb
Wilhelm Heinrich Erb was a German neurologist who was a native of Winnweiler, Rhineland-Palatinate.- Academic career :...

, and most notably Jean-Martin Charcot
Jean-Martin Charcot
Jean-Martin Charcot was a French neurologist and professor of anatomical pathology. He is known as "the founder of modern neurology" and is "associated with at least 15 medical eponyms", including Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis...

, whose studies between 1868 and 1881 were a landmark in the understanding of the disease. Among other advances, he made the distinction between rigidity, weakness and bradykinesia. He also championed the renaming of the disease in honor of James Parkinson.

In 1912 Frederic Lewy
Frederic Lewy
Frederick Henry Lewey was a prominent neurologist. He is perhaps best known for the discovery of Lewy bodies, which are a characteristic indicator of Parkinson's disease and Dementia with Lewy bodies.-Other sources:* Holdorff B., Friedrich Heinrich Lewy and His Work...

 described microscopic particles in affected brains, later named "Lewy bodies
Lewy body
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in Parkinson's disease , Lewy Body Dementia and some other disorders. They are identified under the microscope when histology is performed on the brain....

". In 1919 Konstantin Tretiakoff
Konstantin Tretiakoff
Konstantin Nikolaevitch Tretiakoff was a Russian neuropathologist. He was born in Fergana, Uzbekistan, as a son of military physician, who was member of Pierre Bonvalot's first Pamir expedition. He studied medicine in L'Assistance Publique des Hopitaux de Paris. He received his doctorate in 1919...

 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
Rolf Hassler
Rolf Hassler was a German pathologist who made important discoveries on the pathophisiology and treatment of Parkinson’s disease ....

 in 1938. The underlying biochemical changes in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

 were identified in the 1950s, due largely to the work of Arvid Carlsson
Arvid Carlsson
Arvid Carlsson is a Swedish scientist who is best known for his work with the neurotransmitter dopamine and its effects in Parkinson's disease...

 on the neurotransmitter dopamine and its role on PD. In 1997, alpha-synuclein was found to be the main component of Lewy bodies.

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. Levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...

 was first synthesized in 1911 by Casimir Funk, but it received little attention until the mid 20th century. It entered clinical practice in 1967 and brought about a revolution in the management of PD. By the late 1980s deep brain stimulation
Deep brain stimulation
Deep brain stimulation is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain...

 emerged as a possible treatment.

Research directions

There is little prospect of dramatic new PD treatments expected in a short time frame. Currently active research directions include the search for new animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...

s of the disease and studies of the potential usefulness of gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...

, stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...

 transplants and neuroprotective agents.

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
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...

 MPPP
MPPP
1-Methyl-4-phenyl-4-propionoxypiperidine or Desmethylprodine is an opioid analgesic drug developed in the 1940s by researchers at Hoffmann-La Roche. It is not used in clinical practice, but has been illegally manufactured for recreational drug use...

 led to the discovery of the chemical MPTP
MPTP
MPTP is a neurotoxin precursor to MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain...

 as an agent that causes a parkinsonian syndrome in non-human primates as well as in humans. Other predominant toxin-based models employ the insecticide rotenone
Rotenone
Rotenone is an odorless chemical that is used as a broad-spectrum insecticide, piscicide, and pesticide. It occurs naturally in the roots and stems of several plants such as the jicama vine plant...

, the herbicide paraquat
Paraquat
Paraquat is the trade name for N,N′-dimethyl-4,4′-bipyridinium dichloride, one of the most widely used herbicides in the world. Paraquat, a viologen, is quick-acting and non-selective, killing green plant tissue on contact. It is also toxic to human beings and animals...

 and the fungicide maneb
Maneb
Maneb is a foliate fungicide and is a polymeric complex of manganese with the ethylene bis anionic ligand. It was included in a biocide ban proposed by the Swedish Chemicals Agency and approved by the European Parliament on January 13, 2009....

. Models based on toxins are most commonly used in primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...

s. Transgenic rodent models that replicate various aspects of PD have been developed.

Gene therapy

Gene therapy involves the use of a non-infectious virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

 to shuttle a gene into a part of the brain. The gene used leads to the production of an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 that helps to manage PD symptoms or protects the brain from further damage. In 2010 there were four clinical trials using gene therapy in PD. There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown. One of these reported positive results in 2011.

Neuroprotective treatments

Investigations on neuroprotection are at the forefront of PD research. Several molecules have been proposed as potential treatments. However, none of them have been conclusively demonstrated to reduce degeneration. Agents currently under investigation include anti-apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

s (omigapil, CEP-1347), antiglutamatergics, monoamine oxidase
Monoamine oxidase
L-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...

 inhibitors (selegiline
Selegiline
Selegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A...

, rasagiline
Rasagiline
Rasagiline is an irreversible inhibitor of monoamine oxidase used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. It is selective for MAO type B over type A by a factor of fourteen....

), promitochondrials (coenzyme Q10, creatine
Creatine
Creatine is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of Adenosine triphosphate...

), calcium channel blocker
Calcium channel blocker
A calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with...

s (isradipine
Isradipine
Isradipine is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack...

) and growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....

s (GDNF). Preclinical research also targets alpha-synuclein
Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the...

.

Neural transplantation

Since early in the 1980s, fetal
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...

, porcine
Pig
A pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...

, carotid
Common carotid artery
In human anatomy, the common carotid artery is an artery that supplies the head and neck with oxygenated blood; it divides in the neck to form the external and internal carotid arteries. - Structure :...

 or retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...

l 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.
Although there was initial evidence of mesencephalic
Mesencephalon
The midbrain or mesencephalon is a portion of the central nervous system associated with vision, hearing, motor control, sleep/wake, arousal , and temperature regulation....

 dopamine-producing cell transplants being beneficial, double-blind trials to date indicate that cell transplants produce no long-term benefit. An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...

s. Stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...

 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. Nevertheless, use of fetal stem cells is controversial
Stem cell controversy
The stem cell controversy is the ethical debate primarily concerning the creation, treatment, and destruction of human embryos incident to research involving embryonic stem cells. Not all stem cell research involves the creation, use, or destruction of human embryos...

. It has been proposed that effective treatments may be developed in a less controversial way by use of induced pluripotent stem cell
Induced pluripotent stem cell
Induced pluripotent stem cells, commonly abbreviated as iPS cells or iPSCs are a type of pluripotent stem cell artificially derived from a non-pluripotent cell, typically an adult somatic cell, by inducing a "forced" expression of specific genes....

s taken from adults.

Society and culture

Cost

The costs of PD to society are high, but difficult to calculate exactly due to methodological difficulties in research and differences between countries. 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. The largest share of direct cost comes from inpatient care
Inpatient care
Inpatient care is the care of patients whose condition requires admission to a hospital. Progress in modern medicine and the advent of comprehensive out-patient clinics ensure that patients are only admitted to a hospital when they are extremely ill or are have severe physical...

 and nursing homes, while the share coming from medications is substantially lower. Indirect costs are high, due to reduced productivity and the burden on caregivers. In addition to economic costs, PD reduces quality of life
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...

 of those with the disease and their caregivers.

Advocacy

April 11, the birthday of James Parkinson, has been designated as the world's Parkinson's disease day. A red tulip was chosen by several international organizations as the symbol of the disease in 2005: it represents the James Parkinson Tulip cultivar
Cultivar
A cultivar'Cultivar has two meanings as explained under Formal definition. When used in reference to a taxon, the word does not apply to an individual plant but to all those plants sharing the unique characteristics that define the cultivar. is a plant or group of plants selected for desirable...

, registered in 1981 by a Dutch horticulturalist. Advocacy organizations on the disease include the National Parkinson Foundation
National Parkinson Foundation
The National Parkinson Foundation , founded in 1957, is a national organization whose mission is to improve the quality of care for people with Parkinson's through clinical research, education and outreach on Parkinson’s disease....

, which has provided more than $155 million in care, research and support services since 1982, Parkinson's Disease Foundation
Parkinson's Disease Foundation
The Parkinson's Disease Foundation is a leading national presence in the United States in Parkinson's disease research, education and public advocacy. PDF funds scientific research to find the causes of and a cure for Parkinson's...

, 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; the American Parkinson Disease Association
American Parkinson Disease Association
The American Parkinson Disease Association strives to provide individuals with Parkinson's disease support and education, increase the awareness and boost research on the disease. It was founded in 1961.-External links:*...

, founded in 1961; and the European Parkinson's Disease Association
European Parkinson's Disease Association
The European Parkinson's Disease Association is a non political, non-religious, and non-profit making organisation concerned with the health and welfare of people living with Parkinson's disease and their families and carers....

, founded in 1992.

Notable cases

Among the many famous people with PD, one who has greatly increased the public awareness of the disease is the actor Michael J. Fox
Michael J. Fox
Michael J. Fox, OC is a Canadian American actor, author, producer, activist and voice-over artist. With a film and television career spanning from the late 1970s, Fox's roles have included Marty McFly from the Back to the Future trilogy ; Alex P...

. Fox was diagnosed in 1991 when he was 30, but kept his condition secret from the public for seven years. He has written two autobiographic books in which his fight against the disease plays a major role, and appeared before the United States Congress
United States Congress
The United States Congress is the bicameral legislature of the federal government of the United States, consisting of the Senate and the House of Representatives. The Congress meets in the United States Capitol in Washington, D.C....

 without medication to illustrate the effects of the disease. The Michael J. Fox Foundation
The Michael J. Fox Foundation
The Michael J. Fox Foundation for Parkinson's Research is dedicated to finding a cure for Parkinson's disease through an aggressively funded research agenda and to ensuring the development of improved therapies for those living with Parkinson's today. Established by actor Michael J...

 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. Fox's work led him to be named one of the 100 people
Time 100
Time 100 is an annual list of the 100 most influential people in the world, as assembled by Time. First published in 1999 as a result of a debate among several academics, the list has become an annual event.-History and format:...

 "whose power, talent or moral example is transforming the world" in 2007 by Time magazine
Time (magazine)
Time is an American news magazine. A European edition is published from London. Time Europe covers the Middle East, Africa and, since 2003, Latin America. An Asian edition is based in Hong Kong...

, and he received an honorary doctorate in medicine from Karolinska Institutet
Karolinska Institutet
Karolinska institutet is a medical university in Solna within the Stockholm urban area, Sweden, and one of Europe's largest medical universities...

 for his contributions to research in Parkinson's disease. Another foundation that supports Parkinson's research was established by professional cyclist Davis Phinney
Davis Phinney
Davis Phinney is a former professional road bicycle racer from the United States. He was known as a fast sprinter, and claims to have won the most races in American history. In 1986, he became the first American to win a stage at the Tour de France, while riding on the American-based team 7-Eleven...

. The Davis Phinney Foundation strives to improve the lives of those living with Parkinson's disease by providing them with information and tools. Muhammad Ali
Muhammad Ali
Muhammad Ali is an American former professional boxer, philanthropist and social activist...

 has been called the "world's most famous Parkinson's patient". He was 42 at diagnosis although he already showed signs of Parkinson's when he was 38. Nevertheless, whether he has PD or a parkinsonian syndrome caused by boxing
Dementia pugilistica
Dementia pugilistica is a type of neurodegenerative disease or dementia, which may affect amateur or professional boxers as well as athletes in other sports who suffer concussions...

is still an open question.

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