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Parkinson's disease (PD), or simply Parkinson's, is a
long-term Long-Term Capital Management L.P. (LTCM) was a hedge fund''A financial History of the United States Volume II: 1970–2001'', Jerry W. Markham, Chapter 5: "Bank Consolidation", M. E. Sharpe, Inc., 2002 based in Greenwich, Connecticut, Greenwich, Co ...
degenerative disorderDegenerative disease is the result of a continuous process based on degenerative cell changes, affecting biological tissue, tissues or Organ (anatomy), organs, which will increasingly deteriorate over time. In neurodegenerative diseases, cells of th ...
of the
central nervous system The central nervous system (CNS) is the part of the nervous system In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecu ...

central nervous system
that mainly affects the
motor system The motor system is the set of central Central is an adjective usually referring to being in the center (disambiguation), center of some place or (mathematical) object. Central may also refer to: Directions and generalised locations * Central ...
. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms become more common. The most obvious early symptoms are
tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction Muscle contraction is the activation of tension Tension may refer to: Science * Psychological stress * Tension (physics), a force related to the stretching of an object (the opp ...
, rigidity, slowness of movement, and difficulty with walking.
Cognitive Cognition () refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses many aspects of intellectual function Intellectual functioning refers to the "general men ...
and behavioral problems may also occur with
depression Depression may refer to: Mental health * Depression (mood), a state of low mood and aversion to activity * Mood disorders characterized by depression are commonly referred to as simply ''depression'', including: ** Dysthymia ** Major depressive ...
,
anxiety Anxiety is an emotion Emotions are mental state, psychological states brought on by neurophysiology, neurophysiological changes, variously associated with thoughts, feelings, behavioural responses, and a degree of pleasure or suffering, disp ...

anxiety
, and
apathy Apathy is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as , , , or . An apathetic individual has an absence of interest in or concern about emotional, soci ...

apathy
occurring in many people with PD.
Parkinson's disease dementiaParkinson's disease dementia (PDD) is dementia Dementia occurs as a Syndrome, set of related symptoms when the brain is damaged by injury or disease. The symptoms involve progressive impairments to memory, thinking, and behavior, that affect th ...
becomes common in the advanced stages of the disease. Those with Parkinson's can also have problems with their
sleep Sleep is a naturally recurring state of mind and body, characterized by altered consciousness Consciousness, at its simplest, is or of internal and external existence. Despite millennia of analyses, definitions, explanations and deba ...

sleep
and
sensory systems The sensory nervous system is a part of the nervous system In Biology, biology, the nervous system is a Complex system, highly complex part of an animal that coordinates its Behavior, actions and Sense, sensory information by transmitting a ...
. The motor symptoms of the disease result from the
death of cells Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, or may result from such factors as disease, localized injury, or the ...
in the
substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward system, reward and Motor system, movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts ...

substantia nigra
, a region of the
midbrain The midbrain or mesencephalon is the forward-most portion of the brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain A brain is an organ Organ may refer to: Biology * Organ (anatomy) An organ is a ...

midbrain
, leading to a
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical , CH4; is among the simplest organic compounds. In chemistry Chemistry is t ...

dopamine
deficit. The cause of this cell death is poorly understood, but involves the build-up of
misfolded protein Protein folding is the physical process Physical changes are changes affecting the form of a chemical substance A chemical substance is a form of matter In classical physics and general chemistry, matter is any substance that has mass ...

misfolded protein
s into Lewy bodies in the
neuron A neuron or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapse In the nervous system In biology Biology is the natural science that studies life and living ...

neuron
s. Collectively, the main motor symptoms are also known as
parkinsonism Parkinsonism is a clinical syndrome characterized by tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all ...
or a parkinsonian syndrome. The cause of PD is
unknown Unknown or The Unknown may refer to: Film * The Unknown (1915 comedy film), ''The Unknown'' (1915 comedy film), a silent boxing film * The Unknown (1915 drama film), ''The Unknown'' (1915 drama film) * The Unknown (1927 film), ''The Unknown'' (19 ...
, with both and environmental factors being believed to play a role. Those with a family member affected by PD are at an increased risk of getting the disease, with certain genes known to be inheritable risk factors. Other risk factors are those who have been exposed to certain
pesticide Pesticides are substances that are meant to control pests Pest or The Pest may refer to: Science and medicine * Pest (organism), an animal or plant detrimental to humans or human concerns ** Weed, a plant considered undesirable * Infectious d ...
s and who have prior
head injuries A head injury is any injury that results in trauma to the skull or brain. The terms ''traumatic brain injury'' and ''head injury'' are often used interchangeably in the medical literature. Because head injuries cover such a broad scope of injur ...

head injuries
.
Coffee Coffee is a drink prepared from roasted s, the seeds of from certain s in the ' genus. From the coffee fruit, the seeds are separated to produce a stable, raw product: unroasted ''green coffee''. The seeds are then , a process which transfo ...

Coffee
drinkers,
tea Tea is an aromatic beverage prepared by pouring hot or boiling water over cured A cure is a completely effective treatment for a disease. Cure, or similar, may also refer to: Places * Cure (river), a river in France * Cures, Sabinum, an ...

tea
drinkers, and
tobacco smokers Tobacco smoking is the practice of burning tobacco and ingesting the tobacco smoke that is produced. The smoke may be inhaled, as is done with cigarettes, or simply released from the mouth, as is generally done with tobacco pipes, pipes and ci ...

tobacco smokers
are at a reduced risk. Diagnosis of typical cases is mainly based on symptoms, with motor symptoms being the chief complaint. Tests such as
neuroimaging Neuroimaging or brain imaging is the use of various techniques to either directly or indirectly Medical imaging, image the neuroanatomy, structure, function, or pharmacology of the nervous system. It is a relatively new discipline within medicine ...
(
magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging Medical imaging is the technique and process of imaging Imaging is the representation or reproduction of an object's form; especially a visual representation (i.e., the formation of a ...
or imaging to look at dopamine neuronal dysfunction known as DaT scan) can be used to help rule out other diseases. Parkinson's disease typically occurs in people over the age of 60, of whom about one percent are affected. Males are more often affected than females at a ratio of around 3:2. When it is seen in people before the age of 50, it is called early-onset PD. By 2015, PD affected 6.2 million people and resulted in about 117,400 deaths globally. The average
life expectancy Life expectancy is a statistical measure of the average time an organism is expected to live, based on the year of its birth, its current age, and other demographic Demography (from prefix ''demo-'' from Ancient Greek Ancien ...

life expectancy
following diagnosis is between 7 and 15 years. No cure for PD is known; treatment aims to reduce the effects of the symptoms. is typically with the medications levodopa (
L-DOPA -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology Biology is the natural science that studies life and living organisms, including their anatomy, physical st ...

L-DOPA
), MAO-B inhibitors, or
dopamine agonist A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-( ...
s. As the disease progresses, these medications become less effective, while at the same time producing a
side effect In medicine Medicine is the science Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity, awareness, or understanding of someone or something, such as facts ( descriptive knowledge) ...
marked by involuntary muscle movements. At that time, medications may be used in combination and doses may be increased. Diet and certain forms of rehabilitation have shown some effectiveness at improving symptoms.
Surgery Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical or dental specialty that uses operative manual and instrumental techniques on a person to investigate or t ...
to place
microelectrode A microelectrode is an electrode used in electrophysiology either for recording Action potential, neural signals or for the electrical stimulation of nervous tissue (they were first developed by Ida Henrietta Hyde, Ida Hyde in 1921). Pulled glas ...
s for
deep brain stimulation Deep brain stimulation (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator (sometimes referred to as a "brain pacemaker"), which sends electrical impulses, through implanted electrode An elect ...

deep brain stimulation
has been used to reduce motor symptoms in severe cases where drugs are ineffective. Evidence for treatments for the nonmovement-related symptoms of PD, such as sleep disturbances and emotional problems, is less strong. The disease is named after English doctor
James Parkinson James Parkinson Geological Society of London, FGS (11 April 175521 December 1824) was an English surgeon, apothecary, geologist, palaeontologist and political Activism, activist. He is best known for his 1817 work ''An Essay on the Shaking Palsy' ...

James Parkinson
, who published the first detailed description in ''An Essay on the Shaking Palsy'', in 1817. Public awareness campaigns include World Parkinson's Day (on the birthday of James Parkinson, 11 April) and the use of a red
tulip Tulips (''Tulipa'') are a genus Genus /ˈdʒiː.nəs/ (plural genera /ˈdʒen.ər.ə/) is a taxonomic rank In biological classification In biology Biology is the natural science that studies life and living organisms, inclu ...

tulip
as the symbol of the disease. People with PD who have increased the public's awareness of the condition include boxer
Muhammad Ali Muhammad Ali (; born Cassius Marcellus Clay Jr.; January 17, 1942 – June 3, 2016) was an American professional boxer, activist, entertainer, poet and philanthropist. Nicknamed The Greatest, he is widely regarded as one of the most significa ...

Muhammad Ali
, comedian
Billy Connolly Sir William Connolly (born 24 November 1942) is a Scottish former comedian A comedian or comic is a person who seeks to entertain an audience An audience is a group of people who participate in a show or encounter a work of art ...

Billy Connolly
, actor
Michael J. Fox Michael Andrew Fox (born June 9, 1961), known professionally as Michael J. Fox, is a Canadian-American Canadian Americans is a term that can be applied to American citizens Citizenship is the Status (law), status of a person recognize ...
, Olympic cyclist
Davis Phinney Davis Phinney (born July 10, 1959) is a retired professional road bicycle racer A road is a thoroughfare, route, or way on land between two Location (geography), places that has been Pavement (material), paved or otherwise improved to allow tr ...
, and actor
Alan Alda Alan Alda (; born Alphonso Joseph D'Abruzzo; January 28, 1936) is an American actor. A six-time Emmy Award The Emmy Awards, or Emmys, are awards for artistic and technical merit in the television industry. It is considered one of the fou ...
.


Classification

Parkinson's disease is the most common form of parkinsonism and is sometimes called "
idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent wikt:spontaneous, spontaneous origin. From Ancient Greek, Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approxi ...
parkinsonism", meaning parkinsonism with no identifiable cause. Scientists sometimes refer to PD as a type of
neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neuron A neuron or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells ...
called
synucleinopathy Synucleinopathies (also called α-Synucleinopathies) are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells. There are three main types of synucle ...
due to an abnormal accumulation of the protein
alpha-synuclein Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, while smaller a ...
in the brain. The synucleinopathy classification distinguishes it from other neurodegenerative diseases, such as
Alzheimer's disease Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neuron A neuron or nerve cell is an membrane p ...
, where the brain accumulates a different protein known as the
tau protein The tau proteins (or τ proteins, after the Greek letter with that name) are a group of six highly soluble protein isoforms produced by alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alt ...
. Considerable clinical and pathological overlap exists between
tauopathies Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary Neurofibrillary tangle, tangles (NFTs) in the human brain. Tangles are formed by phosphorylation, hyperpho ...
and synucleinopathies, but differences exist. In contrast to PD, people with Alzheimer's disease most commonly experience memory loss. The cardinal signs of PD (slowness, tremor, stiffness, and postural instability) are not normal features of Alzheimer's. Attempts to classify PD into different subtypes have been made, with focus put on age of onset, progression of symptoms, and dominance of tremor, but none have been adopted.


Signs and symptoms

The most recognizable symptoms in PD are movement ("motor") related. Non-motor symptoms, which include dysfunction (
dysautonomia Dysautonomia or autonomic dysfunction is a condition in which the autonomic nervous system The autonomic nervous system (ANS), formerly the vegetative nervous system, is a division of the peripheral nervous system that supplies smooth muscle an ...
),
neuropsychiatric Neuropsychiatry or Organic Psychiatry is a branch of medicine Medicine is the Art (skill), art, science, and Praxis (process) , practice of caring for a patient and managing the diagnosis, prognosis, Preventive medicine, prevention, therapy, tr ...
problems (mood, cognition, behavior or thought alterations), and sensory (especially altered sense of smell) and sleep difficulties, are also common. Some of these non-motor symptoms may be present at the time of diagnosis.


Motor

Four motor symptoms are considered as
cardinal signs Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...
in PD: tremor, slowness of movement (bradykinesia), rigidity, and postural instability. The most common presenting sign is a coarse, slow
tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction Muscle contraction is the activation of tension Tension may refer to: Science * Psychological stress * Tension (physics), a force related to the stretching of an object (the opp ...
of the hand at rest, which disappears during voluntary movement of the affected arm and in the deeper stages of sleep. It typically appears in only one hand, eventually affecting both hands as the disease progresses. Frequency of PD tremor is between 4 and 6
hertz The hertz (symbol: Hz) is the unit Unit may refer to: Arts and entertainment * UNIT Unit may refer to: Arts and entertainment * UNIT, a fictional military organization in the science fiction television series ''Doctor Who'' * Unit of action ...

hertz
(cycles per second). A feature of tremor is "pill-rolling", the tendency of the index finger and thumb to touch and perform together with a circular movement. The term derives from the similarity between the movement of people with PD and the early pharmaceutical technique of manually making pills.
Bradykinesia Hypokinesia is one of the classifications of movement disorders Movement disorder refers to any clinical syndrome with either an excess of movement or a paucity of voluntary and involuntary movements, unrelated to weakness or spasticity Spastic ...
is found in every case of PD, and is due to disturbances in
motor planningIn psychology and neuroscience Neuroscience (or neurobiology) is the scientific study of the nervous system In Biology, biology, the nervous system is a Complex system, highly complex part of an animal that coordinates its Behavior, actions ...
of movement initiation, and associated with difficulties along the whole course of the movement process, from planning to initiation to execution of a movement. Performance of sequential and simultaneous movement is impaired. Bradykinesia is the most handicapping symptom of Parkinson’s disease, leading to difficulties with everyday tasks such as dressing, feeding, and bathing. It leads to particular difficulty in carrying out two independent motor activities at the same time, and can be made worse by emotional stress or concurrent illnesses. Paradoxically, people with PD can often ride a bicycle or climb stairs more easily than walk on the level. While most physicians may readily notice bradykinesia, formal assessment requires persons to do repetitive movements with their fingers and feet. Rigidity is stiffness and resistance to limb movement caused by increased
muscle tone In physiology Physiology (; ) is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence i ...
, an excessive and continuous contraction of muscles. In parkinsonism, the rigidity can be uniform, known as 'lead-pipe rigidity', or ratchet-y, known as '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 PD, rigidity is often asymmetrical and 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 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. Balance ...
is typical in the later stages of the disease, leading to impaired balance and frequent falls, and secondarily to
bone fracture A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of the bone. In more severe cases, the bone may be broken into several pieces. A bone fracture may be the r ...
s, loss of confidence, and reduced mobility. Instability is often absent in the initial stages, especially in younger people, especially prior to the development of bilateral symptoms. Up to 40% of people diagnosed with PD may experience falls, and around 10% may have falls weekly, with the number of falls being related to the severity of PD. Other recognized motor signs and symptoms include gait and posture disturbances such as festination (rapid shuffling steps and a when walking with no flexed arm swing). Freezing of gait (brief arrests when the feet seem to get stuck to the floor, especially on turning or changing direction), a slurred, monotonous, quiet voice, mask-like facial expression, and handwriting that gets smaller and smaller are other common signs.


Neuropsychiatric

PD can cause
neuropsychiatric Neuropsychiatry or Organic Psychiatry is a branch of medicine Medicine is the Art (skill), art, science, and Praxis (process) , practice of caring for a patient and managing the diagnosis, prognosis, Preventive medicine, prevention, therapy, tr ...
disturbances, which can range from mild to severe. This includes disorders of cognition, mood, behavior, and thought. Cognitive disturbances can occur in the early stages of the disease, and sometimes prior to diagnosis, and increase in prevalence with duration of the disease. The most common cognitive deficit in PD is
executive dysfunction In psychology Psychology is the science of mind and behavior. Psychology includes the study of consciousness, conscious and Unconscious mind, unconscious phenomena, as well as feeling and thought. It is an academic discipline of immense sc ...
, which can include problems with planning,
cognitive flexibility Cognitive flexibility is an intrinsic property of a cognitive system often associated with the mental ability to adjust its activity and content, switch between different task rules and corresponding behavioral responses, maintain multiple conc ...
, abstract thinking, rule acquisition, inhibiting inappropriate actions, initiating appropriate actions,
working memory Working memory is a cognitive system with a limited capacity that can hold information temporarily. Working memory is important for reasoning and the guidance of decision-making and behavior. Working memory is often used synonymously with short-te ...
, and control of attention. Other cognitive difficulties include slowed cognitive processing speed, impaired
recall Recall may refer to: * Recall (bugle call), a signal to stop * Recall (information retrieval), a statistical measure * ReCALL (journal), ''ReCALL'' (journal), an academic journal about computer-assisted language learning * Recall (memory) * Recal ...
, and impaired perception and estimation of time. 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 dementia compared to the general population. Up to 78% of people with PD have Parkinson's disease dementia. The prevalence of dementia increases with age, and to a lesser degree, duration of the disease. Dementia is associated with a reduced
quality of life Quality of life (QOL) is defined by the World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations United Nations Specialized Agencies are autonomous organizations working with the United N ...

quality of life
in people with PD and their
caregiver A caregiver is a paid or unpaid member of a person's social network A social network is a social structure made up of a set of social actors (such as individuals or organizations), sets of Dyad (sociology), dyadic ties, and other Social rela ...
s, increased mortality, and a higher probability of needing
nursing home care A nursing home is a facility for the residential care of elderly or disabled people. Nursing homes may also be referred to as skilled nursing facility (SNF), long-term care facilities, old people's homes, care homes, rest homes, convalescent ho ...
. Impulse-control disorders, including pathological gambling, compulsive sexual behavior, binge eating, compulsive shopping, and reckless generosity, can be caused by medication, particularly orally active dopamine agonists. The dopamine dysregulation syndrome – with wanting of medication leading to overuse – is a rare complication of levodopa use.
Punding Punding is a term that was coined originally to describe complex prolonged, purposeless, and stereotyped behaviour in phenmetrazine and chronic amphetamine users, by Swedish forensic psychiatrist G. Rylander, in 1968. It was later described in Par ...

Punding
, in which complicated, repetitive, aimless, stereotyped behaviors occur for many hours, is another disturbance caused by anti-Parkinson medication.


Psychosis

Psychosis Psychosis is an abnormal condition of the mind that results in difficulties determining what is Reality, real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are thought disord ...
can be considered a symptom with a prevalence at its widest range from 26 to 83%.
Hallucination A hallucination is a perception Perception (from the Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally spoken in the area around Rom ...

Hallucination
s or
delusion A delusion is a false fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or some ot ...

delusion
s occur in about 50% of people with PD over the course of the illness, and may herald the emergence of dementia. These range from minor hallucinations – "sense of passage" (something quickly passing beside the person) or "sense of presence" (the perception of something/someone standing just to the side or behind the person) – to full blown vivid, formed visual hallucinations and
paranoid Paranoia is an instinct or thought process which is believed to be heavily influenced by anxiety or fear Fear is an emotion induced by perceived danger or threat, which causes physiological changes and ultimately behavioral changes, such as ...

paranoid
ideation. Auditory hallucinations are uncommon in PD, and are rarely described as voices. Psychosis is now believed to be an integral part of the disease. A psychosis with delusions and associated
delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline mental functioning, that develops over a short period of time, typically hours to days. Delirium is a syndrome A syndrome is a set of me ...
is a recognized complication of anti-Parkinson drug treatment and may also be caused by urinary-tract infections (as frequently occurs in the fragile elderly), but drugs and infection are not the only factors, and underlying brain pathology or changes in neurotransmitters or their receptors (e.g., acetylcholine, serotonin) are also thought to play a role in psychosis in PD.


Behavior and mood

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 may refer to: Mental health * Depression (mood), a state of low mood and aversion to activity * Mood disorders characterized by depression are commonly referred to as simply ''depression'', including: ** Dysthymia ** Major depressive ...
,
apathy Apathy is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as , , , or . An apathetic individual has an absence of interest in or concern about emotional, soci ...

apathy
, and
anxiety Anxiety is an emotion Emotions are mental state, psychological states brought on by neurophysiology, neurophysiological changes, variously associated with thoughts, feelings, behavioural responses, and a degree of pleasure or suffering, disp ...

anxiety
. Depression has been estimated to appear in 20 to 35% of people with PD, and can appear at any stage of the disease. It can manifest with symptoms that are common to the disease process (fatigue, insomnia, and difficulty with concentration), which makes diagnosis difficult. The imbalance and changes in
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical , CH4; is among the simplest organic compounds. In chemistry Chemistry is t ...

dopamine
,
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter Monoamine neurotransmitters are s and s that contain one group connected to an by a two-carbon chain (such as -CH2-CH2-). Examples are , and . All monoamines are ...

serotonin
, and
noradrenergic Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone and neurotransmitter. The name "noradrenalin ...

noradrenergic
hormones are known to be a primary cause of depression in PD-affected people. Another cause is the functional impairment that is caused by the disease. Symptoms of depression can include loss of interest, sadness, guilt, feelings of helplessness/hopelessness/guilt, and suicidal ideation.
Suicidal ideation Suicidal ideation (or suicidal thoughts) is thinking about, considering, or planning suicide. It is not a diagnosis, but is a symptom of some mental disorder A mental disorder, also called a mental illness or psychiatric disorder, is a beha ...
in PD-affected people is higher than in the general population, but suicidal attempts themselves are lower than in people with depression without PD. Risk factors for depression in PD can include disease onset under age 50, being a woman, previous history of depression, severe motor symptoms, and others.
Anxiety Anxiety is an emotion Emotions are mental state, psychological states brought on by neurophysiology, neurophysiological changes, variously associated with thoughts, feelings, behavioural responses, and a degree of pleasure or suffering, disp ...
has been estimated to have a prevalence in PD-affected people usually around 30–40% (60% has been found). Anxiety can often be found during "off" periods (times when medication is not working as well as it did before) with PD-affected people suffering from panic attacks more frequently compared to the general population. Both anxiety and depression have been found to be associated with decreased quality of life. Symptoms can range from mild and episodic to chronic with potential causes being abnormal
gamma-aminobutyric acid ''gamma-''Aminobutyric acid, or γ-aminobutyric acid , or GABA , is the chief inhibitory An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potent ...
levels and embarrassment or fear about symptoms or disease. Risk factors for anxiety in PD are disease onset under age 50, women, and "off" periods.
Apathy Apathy is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as , , , or . An apathetic individual has an absence of interest in or concern about emotional, soci ...

Apathy
and
anhedonia Anhedonia is a diverse array of deficits in hedonic Hedonism refers to a family of theories, all of which have in common that ''pleasure'' plays a central role in them. ''Psychological'' or ''motivational hedonism'' claims that human behavio ...
can be defined as a loss of motivation and an impaired ability to experience pleasure, respectively. They are symptoms classically associated with depression, but they differ in PD-affected people in treatment and mechanism, and do not always occur with depression. Apathy presents in around 16.5–40%. Symptoms of apathy include reduced initiative/interests in new activities or the world around them, emotional indifference, and loss of affection or concern for others. Apathy is associated with deficits in cognitive functions including executive and verbal memory.


Other

Sleep disorder A sleep disorder, or somnipathy, is a medical disorder A disease is a particular abnormal condition that negatively affects the structure A structure is an arrangement and organization of interrelated elements in a material object or ...
s are a feature of the disease and can be worsened by medications. Symptoms can manifest as daytime
drowsiness Somnolence (alternatively "sleepiness" or "drowsiness") is a state of strong desire for sleep Sleep is a naturally recurring state of mind and body, characterized by altered consciousness , an English Paracelsian physician Consciousness, a ...
(including sudden sleep attacks resembling
narcolepsy Narcolepsy is a long-term Long-Term Capital Management L.P. (LTCM) was a hedge fund''A financial History of the United States Volume II: 1970–2001'', Jerry W. Markham, Chapter 5: "Bank Consolidation", M. E. Sharpe, Inc., 2002 based in Green ...
), disturbances in
Rapid eye movement sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep Sleep is a naturally recurring state of mind and body, characterized by altered consciousness Consciousness, at its simplest, is or of internal and external ...
, or
insomnia Insomnia, also known as sleeplessness, is a sleep disorder A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and ...

insomnia
. REM behavior disorder, in which people act out dreams, sometimes injuring themselves or their bed partner, may begin many years before the development of motor or cognitive features of PD or
dementia with Lewy bodies Dementia with Lewy bodies (DLB) is a type of dementia Dementia manifests as a set of related symptoms, which usually surface when the brain is damaged by injury or disease. The symptoms Signs and symptoms are the observed or detectable s ...
. Alterations in the autonomic nervous system can lead to
orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure Blood pressure (BP) is the pressure Pressure (symbol: ''p'' or ''P'') is the force In physics Physics (fr ...
(low blood pressure upon standing),
oily skin The human skin is the outer covering of the body and is the largest organ of the integumentary system The integumentary system is the set of organs forming the outermost layer of an animal's body. It comprises the skin and its appendages, ac ...
, excessive sweating,
urinary incontinence Urinary incontinence (UI), also known as involuntary urination, is any uncontrolled leakage of urine. It is a common and distressing problem, which may have a large impact on quality of life Quality of life (QOL) is defined by the World Healt ...

urinary incontinence
, and altered sexual function. Constipation and Intestinal pseudoobstruction, impaired stomach emptying (gastric dysmotility) can be severe enough to cause discomfort and even endanger health. Changes in perception may include an impaired sense of smell, disturbed vision, pain, and paresthesia (tingling and numbness). All of these symptoms can occur years before diagnosis of the disease.


Causes

Many risk factors have been proposed, sometimes in relation to theories concerning possible mechanisms of the disease; however, none has been proven conclusively. The most frequently replicated relationships are an increased risk in those exposed to pesticides, and a reduced risk in smokers. A possible link exists between PD and ''Helicobacter pylori'' infection that can prevent the absorption of some drugs, including levodopa.


Genetic

Research indicates that PD is the product of a complex interaction of genetic and environmental factors. Around 15% of individuals with PD have a First-degree relatives, first-degree relative who has the disease, and 5–10% of people with PD are known to have forms of the disease that occur because of a mutation in one of several specific genes. Harboring one of these gene mutations may not lead to the disease; susceptibility factors put the individual at an increased risk, often in combination with other risk factors, which also affect age of onset, severity and progression. At least 11 autosomal dominant and 9 autosomal recessive gene mutations have been implicated in the development of PD. The autosomal dominant genes include Alpha-synuclein, ''SNCA'','' PARK3'', Ubiquitin carboxy-terminal hydrolase L1, ''UCHL1'', ''LRRK2'', TNRC15, ''GIGYF2'', HtrA serine peptidase 2, ''HTRA2'', Eukaryotic translation initiation factor 4 gamma 1, ''EIF4G1'', ''TMEM230'', ''CHCHD2'', ''RIC3'', and ''VPS35''. Autosomal recessive genes include ''Parkin (ligase), PRKN, PINK1, PARK7, ATP13A2, PLA2G6, FBXO7, Auxilin, DNAJC6, SYNJ1,'' and ''VPS13C''. Some genes are Sex linkage, X-linked or have unknown inheritance pattern; those include ''PARK10, PARK12'', and ''PARK16''. A DiGeorge syndrome, 22q11 deletion is also known to be associated with PD. An autosomal dominant form has been associated with mutations in the'' LRP10'' gene. About 5% of people with PD have mutations in the ''GBA1'' gene. These mutations are present in less than 1% of the unaffected population. The risk of developing PD is increased 20–30 fold if these mutations are present. PD associated with these mutations has the same clinical features, but an earlier age of onset and a more rapid cognitive and motor decline. This gene encodes glucocerebrosidase. Low levels of this enzyme cause Gaucher's disease. ''SNCA'' gene mutations are important in PD because the protein this gene encodes,
alpha-synuclein Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, while smaller a ...
, is the main component of the Lewy body, Lewy bodies that accumulate in the brains of people with PD. Alpha-synuclein activates ataxia telangiectasia mutated, a major DNA damage (naturally occurring), DNA damage-repair signaling kinase. In addition, alpha-synuclein activates the non-homologous end joining DNA repair pathway. The aggregation of alpha-synuclein in Lewy bodies appears to be a link between reduced DNA repair and brain-cell death in PD. Mutations in some genes, including ''SNCA'', ''LRRK2'', and ''GBA'', have been found to be risk factors for "sporadic" (nonfamilial) PD. Mutations in the gene ''LRRK2'' are the most common known cause of familial and sporadic PD, accounting for around 5% of individuals with a family history of the disease and 3% of sporadic cases. A mutation in ''GBA'' presents the greatest genetic risk of developing Parkinsons disease. Several Parkinson-related genes are involved in the function of lysosomes, organelles that digest cellular waste products. Some cases of PD may be caused by Lysosomal storage disease, lysosomal disorders that reduce the ability of cells to break down alpha-synuclein.


Non-genetic

Exposure to pesticides and a history of head injury have each been linked with PD, but the risks are modest. Never drinking caffeinated beverages is also associated with small increases in risk of developing PD. Some toxins can cause parkinsonism, including manganese and carbon disulfide. Medical drugs implicated in cases of parkinsonism. Drug-induced parkinsonism is normally reversible by stopping the offending agent, such as [phenothiazines (chlorpromazine, promazine, etc.); butyrophenones (haloperidol, benperidol, etc.); metoclopramide and Tetrabenazine. MPTP, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a drug known for causing irreversible parkinsonism that is commonly used in animal-model research. Low concentrations of Uric acid, urate in the blood is associated with an increased risk of PD. Other identifiable causes of parkinsonism include infections and metabolic derangement. Several neurodegenerative disorders also may present with parkinsonism, and are sometimes referred to as "atypical parkinsonism" or Parkinson-plus syndrome, "Parkinson plus" syndromes (illnesses with parkinsonism plus some other features distinguishing them from PD). They include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies. Dementia with Lewy bodies is another synucleinopathy and it has close pathological similarities with PD, especially with the subset of PD cases with dementia known as
Parkinson's disease dementiaParkinson's disease dementia (PDD) is dementia Dementia occurs as a Syndrome, set of related symptoms when the brain is damaged by injury or disease. The symptoms involve progressive impairments to memory, thinking, and behavior, that affect th ...
. The relationship between PD and DLB is complex and incompletely understood. They may represent parts of a continuum, with variable distinguishing clinical and pathological features, or they may prove to be separate diseases. Vascular parkinsonism is the phenomenon of the presence of Parkinson's disease symptoms combined with findings of vascular events (such as a Stroke, cerebral stroke). The damaging of the dopaminergic pathways is similar in cause for both vascular parkinsonism and idiopathic PD, so they can present with many of the same symptoms. Differentiation can be made with careful bedside examination, history evaluation, and imaging.


Pathophysiology

The main Pathology, pathological characteristics of PD are cell death in the brain's basal ganglia (affecting up to 70% of the dopaminergic, dopamine-secreting neurons in the
substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward system, reward and Motor system, movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts ...

substantia nigra
pars compacta by the end of life). In Parkinson's disease, alpha-synuclein becomes Protein folding, misfolded and Protein aggregation, clump together with other alpha-synuclein. Cells are unable to remove these clumps, and the alpha-synuclein becomes Cytotoxicity, cytotoxic, damaging the cells. These clumps can be seen in neurons under a microscope and are called Lewy bodies. Loss of neurons is accompanied by the death of astrocytes (star-shaped neuroglia, glial cells) and a significant increase in the number of microglia (another type of glial cell) in the substantia nigra. Braak staging is a way to explain the progression of the parts of the brain affected by PD. According to this staging, PD starts in the medulla and the olfactory bulb before moving to the substantia nigra pars compacta and the rest of the midbrain/basal forebrain. Movement symptom onset is associated when the disease begins to affect the substantia nigra pars compacta. Five major pathways in the brain connect other brain areas with the basal ganglia. These are known as the Motor cortex, motor, Frontal eye fields, oculomotor, Cerebral cortex#Association areas, associative, Limbic system, limbic, and Orbitofrontal cortex, 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, Inhibitory postsynaptic potential, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus, the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output. Drugs that are used to treat PD, conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias.


Brain cell death

Brain cells could be lost by several proposed mechanisms. One mechanism consists of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. This insoluble protein accumulates inside neurons forming Inclusion bodies, inclusions called Lewy bodies. According to the Braak staging, a classification of the disease based on pathological findings proposed by Heiko Braak, Lewy bodies first appear in the olfactory bulb, medulla oblongata, and pontine tegmentum; individuals at this stage may be asymptomatic or may have early nonmotor symptoms (such as loss of sense of smell, or some sleep or automatic dysfunction). As the disease progresses, Lewy bodies develop in the substantia nigra, areas of the
midbrain The midbrain or mesencephalon is the forward-most portion of the brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain A brain is an organ Organ may refer to: Biology * Organ (anatomy) An organ is a ...

midbrain
and basal forebrain, and finally, the neocortex. These brain sites are the main places of neuronal degeneration in PD, but Lewy bodies may not cause cell death and they may be protective (with the abnormal protein sequestered or walled off). Other forms of alpha-synuclein (e.g., oligomers) that are not aggregated in Lewy bodies and Lewy body, Lewy neurites may actually be the toxic forms of the protein. In people with dementia, a generalized presence of Lewy bodies is common in cortical areas. Neurofibrillary tangles and senile plaques, characteristic of Alzheimer's disease, are not common unless the person is demented. Other cell-death mechanisms include Proteasome, proteasomal and Lysosome, lysosomal systems dysfunction and reduced Mitochondrion, mitochondrial activity. Iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. It may be related to oxidative stress, protein aggregation, and neuronal death, but the mechanisms are not fully understood.


Diagnosis

A physician initially assesses for PD with a careful medical history and neurological examination. Focus is put on confirming motor symptoms (bradykinesia, rest tremor, etc.) and supporting tests with clinical diagnostic criteria. The finding of Lewy bodies in the midbrain on autopsy is usually considered final proof that the person had PD. The clinical course of the illness over time may reveal it is not PD, requiring that the clinical presentation be periodically reviewed to confirm the accuracy of the diagnosis. Multiple causes can occur for parkinsonism or diseases that look similar. Stroke, certain medications, and toxins can cause "secondary parkinsonism" and need to be assessed during visit. Parkinson-plus syndromes, such as progressive supranuclear palsy and multiple system atrophy, must also be considered and Differential diagnosis, ruled out appropriately due to different treatment and disease progression (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. Medical organizations have created Medical diagnosis#Diagnostic criteria, 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 Queen Square Brain Bank for Neurological Disorders and the U.S. National Institute of Neurological Disorders and Stroke. The Queen Square Brain Bank criteria require slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. Other possible causes of these symptoms need to be ruled out. Finally, three or more of the following supportive 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, the clinical course of at least ten years and appearance of dyskinesias induced by the intake of excessive levodopa. Assessment of sudomotor function through electrochemical skin conductance, can be helpful in diagnosing
dysautonomia Dysautonomia or autonomic dysfunction is a condition in which the autonomic nervous system The autonomic nervous system (ANS), formerly the vegetative nervous system, is a division of the peripheral nervous system that supplies smooth muscle an ...
. Magnetic resonance imaging has become more accurate in diagnosis of the disease over time, specifically through iron-sensitive Relaxation (NMR)#T2* and magnetic field inhomogeneity, T2* and susceptibility weighted imaging sequences at a magnetic field strength of at least 3T, both of which can demonstrate absence of the characteristic 'swallow tail' imaging pattern in the dorsolateral substantia nigra. In a meta-analysis, absence of this pattern was highly Sensitivity and specificity#Sensitivity, sensitive and Sensitivity and specificity#Specificity, specific for the disease. A 2020 meta-analysis found that MRI sequence#Neuromelanin imaging, neuromelanin-MRI had a favorable diagnostic performance in discriminating individuals with Parkinson's from healthy subjects. Diffusion MRI has shown potential in distinguishing between PD and Parkinson-plus syndromes, though its diagnostic value is still under investigation. CT and MRI are also used to rule out other diseases that can be secondary causes of parkinsonism, most commonly encephalitis and stroke, chronic ischemic insults, as well as less frequent entities such as basal ganglia Neoplasm, tumors and hydrocephalus. The metabolism, metabolic activity of dopamine transporters in the basal ganglia can be directly measured with positron emission tomography and single-photon emission computed tomography scans, with the DaTSCAN being a common proprietary version of this study. It has shown high agreement with clinical diagnoses of PD. Reduced dopamine-related activity in the basal ganglia can help exclude drug-induced Parkinsonism. This finding is not entirely specific, however, and can be seen with both PD and Parkinson-plus disorders. In the United States, DaTSCANs are only Food and Drug Administration, FDA approved to distinguish PD or Parkinsonian syndromes from essential tremor. Iodine-123-meta-iodobenzylguanidine myocardial scintigraphy can help find denervation of the muscles around the heart, which can support a PD diagnosis.


Differential diagnosis

Secondary parkinsonism – The multiple causes of parkinsonism can be differentiated between with careful history, physical examination, and appropriate imaging. This topic is further discussed in the causes section Parkinson's disease#Causes, here. Parkinson-plus syndrome – Multiple diseases can be considered part of the Parkinson's plus group, including corticobasal syndrome, multiple system atrophy, progressive supranuclear palsy, and Dementia with Lewy bodies, dementia with lewy bodies. Differential diagnosis can be narrowed down with careful history and physical (especially focused on onset of specific symptoms), progression of the disease, and response to treatment. Some key features between them: * Corticobasal syndrome - levodopa-resistance, myoclonus, dystonia, corticosensory loss, apraxia, and non-fluent aphasia * Multiple system atrophy – levodopa resistance, rapidly progressive, autonomic failure, stridor, present Plantar reflex, Babinski sign, cerebellar ataxia, and specific MRI findings * Progressive supranuclear palsy – levodopa resistance, restrictive vertical gaze, specific MRI findings, and early and different postural difficulties * Dementia with Lewy bodies – levodopa resistance, cognitive predominance before motor symptoms, and fluctuating cognitive symptoms, (visual hallucinations are very common in this disease, but PD patients also have them) *Essential tremor – This can at first look like parkinsonism, but has key differentiators. In essential tremor, the tremor gets worse with action (whereas in PD, it gets better), a lack of other symptoms is common in PD, and normal DatSCAN is seen. Other conditions that can have similar presentations to PD include: * Arthritis * Creutzfeldt–Jakob disease * Dystonia * Major depressive disorder, Depression * Fragile X-associated tremor/ataxia syndrome * Frontotemporal dementia and parkinsonism linked to chromosome 17 * Huntington’s disease * Basal ganglia calcification, Idiopathic basal ganglia calcification * Neurodegeneration with brain iron accumulation * Normal-pressure hydrocephalus * Obsessional slowness * Psychogenic parkinsonism * Wilson’s disease


Prevention

Exercise in middle age may reduce the risk of PD later in life. Caffeine also appears protective with a greater decrease in risk occurring with a larger intake of caffeinated beverages such as coffee. Antioxidants, such as Vitamin C, vitamins C and Vitamin E, E, 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 acids have been contradictory, with various studies reporting protective, risk-increasing, or no effects. There have been preliminary indications that the use of Nonsteroidal anti-inflammatory drug, anti-inflammatory drugs and calcium channel blockers may be protective. A 2010 meta-analysis found that nonsteroidal anti-inflammatory drugs (apart from aspirin), have been associated with at least a 15% (higher in long-term and regular users) reduction in the incidence of the development of PD.


Management

No cure for Parkinson's disease is known. Medications, surgery, and Physical therapy, physical treatment may provide relief, improve the quality of a person's life, and are much more effective than treatments available for other neurological disorders such as Alzheimer's disease, motor neuron disease, and Parkinson-plus syndromes. The main families of drugs useful for treating motor symptoms are L-DOPA, levodopa always combined with a Aromatic L-amino acid decarboxylase inhibitor, dopa decarboxylase inhibitor and sometimes also with a COMT inhibitor,
dopamine agonist A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-( ...
s, and MAO-B inhibitors. The stage of the disease and the age at disease onset determine which group is most useful. Braak staging of PD uses six stages that can identify early, middle, and late stages. The initial stage in which some disability has already developed and requires pharmacological treatment is followed by later stages associated with the development of complications related to levodopa usage, and a third stage when symptoms unrelated to dopamine deficiency or levodopa treatment may predominate. Treatment in the first stage aims for an optimal trade-off between symptom control and treatment side effects. The start of levodopa treatment may be postponed by initially using other medications, such as MAO-B inhibitors and dopamine agonists, instead, in the hope of delaying the onset of complications due to levodopa use. Levodopa is still the most effective treatment for the motor symptoms of PD, though, and should not be delayed in people when their quality of life is impaired. Levodopa-related dyskinesias correlate more strongly with duration and severity of the disease than duration of levodopa treatment, so delaying this therapy may not provide much longer dyskinesia-free time than early use. In later stages, the aim is to reduce PD symptoms, while controlling fluctuations in the effect of the medication. Sudden withdrawals from medication or its overuse must be managed. When oral medications are not enough to control symptoms, surgery,
deep brain stimulation Deep brain stimulation (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator (sometimes referred to as a "brain pacemaker"), which sends electrical impulses, through implanted electrode An elect ...

deep brain stimulation
, subcutaneous waking-day apomorphine infusion, and enteral administration, enteral dopa pumps may be useful. Late-stage PD presents many challenges requiring a variety of treatments, including those for psychiatric symptoms particularly depression, orthostatic hypotension, bladder dysfunction, and erectile dysfunction. In the final stages of the disease, palliative care is provided to improve a person's quality of life. A 2020 Cochrane review found no certain evidence that cognitive training is beneficial for people with Parkinson's disease, dementia or mild cognitive impairment. The findings are based on low certainty evidence of seven studies.


Medications


Levodopa

The motor symptoms of PD are the result of reduced dopamine production in the brain's basal ganglia. Dopamine does not cross the blood-brain barrier, so it cannot be taken as a medicine to boost the brain's depleted levels of dopamine, but a Precursor (chemistry), precursor of dopamine, levodopa, can pass through to the brain, where it is readily converted to dopamine, and administration of levodopa temporarily diminishes the motor symptoms of PD. Levodopa has been the most widely used PD treatment for over 40 years. Only 5–10% of levodopa crosses the blood–brain barrier. Much of the remainder is metabolized to dopamine elsewhere in the body, causing a variety of side effects, including nausea, vomiting, and orthostatic hypotension. Carbidopa and benserazide are Aromatic L-amino acid decarboxylase inhibitor, dopa decarboxylase inhibitors that do not cross the blood-brain barrier and inhibit the conversion of levodopa to dopamine outside the brain, reducing side effects and improving the availability of levodopa for passage into the brain. One of these drugs is usually taken along with levodopa, often combined with levodopa in the same pill. Levodopa use leads in the long term to the development of complications, such as involuntary movements (dyskinesias) and fluctuations in the effectiveness of the medication. When fluctuations occur, a person can cycle through phases with good response to medication and reduced PD symptoms ("on" state), and phases with poor response to medication and significant PD symptoms ("off" state). Using lower doses of levodopa may reduce the risk and severity of these levodopa-induced complications. A former strategy to reduce levodopa-related dyskinesia and fluctuations was to withdraw levodopa medication for some time. This is now discouraged, since it can bring on dangerous side effects such as neuroleptic malignant syndrome. Most people with PD eventually need levodopa and later develop levodopa-induced fluctuations and dyskinesias. Modified-release dosage (medicine), Controlled-release (CR) versions of levodopa are available. Older CR levodopa preparations have poor and unreliable Absorption (pharmacokinetics), absorption and bioavailability and have not demonstrated improved control of PD motor symptoms or a reduction in levodopa-related complications when compared to immediate-release preparations. A newer extended-release levodopa preparation does seem to be more effective in reducing fluctuations, but in many people, problems persist. Intestinal infusions of levodopa (Duodopa) can result in striking improvements in fluctuations compared to oral levodopa when the fluctuations are due to insufficient uptake caused by gastroparesis. Other oral, longer-acting formulations are under study, and other modes of delivery (inhaled, transdermal) are being developed.


COMT inhibitors

During the course of PD, affected people can experience what is known as a "wearing off phenomenon", where they have a recurrence of symptoms after a dose of levodopa, but right before their next dose. Catechol-O-methyltransferase (COMT) is a protein that degrades levodopa before it can cross the Blood–brain barrier, blood-brain barrier and these inhibitors allow for more levodopa to cross. They are normally not used in the management of early symptoms, but can be used in conjunction with levodopa/carbidopa when a person is experiencing the "wearing off phenomenon" with their motor symptoms. Three COMT inhibitors are available to treat adults with PD and end-of-dose motor fluctuations – opicapone, entacapone, and tolcapone. Tolcapone has been available for several years, but its usefulness is limited by possible liver damage complications, so requires liver-function monitoring. Entacapone and opicapone have not been shown to cause significant alterations to liver function. Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa. Opicapone is a once-daily COMT inhibitor.


Dopamine agonists

Several
dopamine agonist A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-( ...
s that bind to dopamine receptors in the brain have similar effects to levodopa. These were initially used as a complementary therapy to levodopa for individuals experiencing levodopa complications (on-off fluctuations and dyskinesias); they are now mainly used on their own as first therapy for the motor symptoms of PD with the aim of delaying the initiation of levodopa therapy, thus delaying the onset of levodopa's complications. Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride. Though dopamine agonists are less effective than levodopa at controlling PD motor symptoms, they are usually effective enough to manage these symptoms in the first years of treatment. Dyskinesias due to dopamine agonists are rare in younger people who have PD, but along with other complications, become more common with older age at onset. Thus, dopamine agonists are the preferred initial treatment for younger-onset PD, and levodopa is preferred for older-onset PD. Dopamine agonists produce significant, although usually mild, side effects, including drowsiness, 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. Agonists have been related to impulse-control disorders (such as compulsive sexual activity, eating, gambling, and shopping) even more strongly than levodopa. They tend to be more expensive than levodopa. Apomorphine, a dopamine agonist, may be used to reduce off periods and dyskinesia in late PD. It is administered only by intermittent injections or continuous Hypodermoclysis, subcutaneous infusions. Since secondary effects such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be closely monitored. Two dopamine agonists administered through skin patches (lisuride and rotigotine) are useful for people in the initial stages and possibly to control off states in those in advanced states.


MAO-B inhibitors

MAO-B inhibitors (safinamide, selegiline and rasagiline) increase the amount of dopamine in the basal ganglia by inhibiting the activity of monoamine oxidase B, an enzyme that breaks down dopamine. They have been found to help alleviate motor symptoms when used as monotherapy (on their own); when used in conjunction with levodopa, they reduce the time spent in the "off" phase. Selegiline has been shown to delay the need for levodopa commencement, suggesting that it might be neuroprotective and slow the progression of the disease (but this has not been proven). An initial study indicated that selegiline in combination with levodopa increased the risk of death, but this has been refuted. Common side effects are nausea, dizziness, insomnia, sleepiness, and (in selegiline and rasagiline) orthostatic hypotension. Along with dopamine, MAO-Bs are known to increase serotonin, so care must be taken when used with certain antidepressants due to a potentially dangerous condition known as serotonin syndrome.


Other drugs

Other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms, but 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. Several drugs have been used to treat some of these problems. Examples are the use of quetiapine for psychosis, Acetylcholinesterase inhibitor, cholinesterase inhibitors for dementia, and modafinil for excessive daytime sleepiness. In 2016, pimavanserin was approved for the management of PD psychosis. Doxepin and rasagline may reduce physical fatigue in PD.


Surgery

Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa, the number of operations has declined. Studies in the past few decades have led to great improvements in surgical techniques, so 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 (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator (sometimes referred to as a "brain pacemaker"), which sends electrical impulses, through implanted electrode An elect ...

deep brain stimulation
(DBS). Target areas for DBS or lesions include the thalamus, globus pallidus, or subthalamic nucleus. DBS involves the implantation of a medical device called a Neurostimulation, neurostimulator, which sends electrical impulses to specific parts of the brain. DBS is recommended for people who have PD with 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 intentional formation of lesions to suppress overactivity of specific wikt:subcortical, subcortical areas. For example, pallidotomy involves surgical destruction of the globus pallidus to control dyskinesia. Four areas of the brain have been treated with neural stimulators in PD. These are the globus pallidus interna, thalamus, subthalamic nucleus, and pedunculopontine nucleus. DBS of the globus pallidus interna improves motor function, while DBS of the thalamic DBS improves tremor, but has little effect on bradykinesia or rigidity. DBS of the subthalamic nucleus is usually avoided if a history of depression or neurocognitive impairment is present. DBS of the subthalamic nucleus is associated with a reduction in medication. Pedunculopontine nucleus DBS remains experimental at present. Generally, DBS is associated with 30–60% improvement in motor score evaluations.


Rehabilitation

Exercise programs are recommended in people with PD. Some evidence shows that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality. Regular physical exercise with or without physical therapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life. When an exercise program is performed under the supervision of a physiotherapist, more improvements occur in motor symptoms, mental and emotional functions, daily living activities, and quality of life compared to a self-supervised exercise program at home. Clinical exercises may be an effective intervention targeting overall well-being of individuals with Parkinson's. Improvement in motor function and depression may happen. In improving flexibility and range of motion for people experiencing rigidity, generalized relaxation techniques such as gentle rocking have been found to decrease excessive muscle tension. Other effective techniques to promote relaxation include slow rotational movements of the extremities and trunk, rhythmic initiation, diaphragmatic breathing, and meditation techniques. As for gait and addressing the challenges associated with the disease such as hypokinesia, shuffling, and decreased arm swing, physiotherapists have a variety of strategies to improve functional mobility and safety. Areas of interest concerning gait during rehabilitation programs focus on improving gait speed, the base of support, stride length, and trunk and arm-swing movement. Strategies include using 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 people with primary muscular weakness and weakness related to inactivity with mild to moderate PD, but reports show a significant interaction between strength and the time the medications were taken. Therefore, people with PD should perform exercises 45 minutes to one hour after medications when they are at their best. Also, due to the forward flexed posture, and respiratory dysfunctions in advanced PD, deep diaphragmatic breathing exercises are beneficial in improving chest-wall mobility and vital capacity. Exercise may improve constipation. If exercise reduces physical fatigue in PD remains unclear. Strength training exercise has been shown to increase manual dexterity in PD patients after exercising with manual putty. This positively affects everyday life when gripping for PD patients. One of the most widely practiced Speech therapy, treatments for speech disorders associated with PD is the Lee Silverman voice treatment (LSVT). Speech therapy and specifically LSVT may improve speech. Occupational therapy (OT) aims to promote health and quality of life by helping people with the disease to participate in as many of their Daily living skills, daily living activities as possible. Few studies have been conducted on the effectiveness of OT, and their quality is poor, although with some indication that it may improve motor skills and quality of life for the duration of the therapy.


Palliative care

Palliative care is specialized medical care for people with serious illnesses, including Parkinson's. The goal of this speciality is to improve quality of life for both the person with PD and the family by providing relief from the symptoms, pain, and stress of illnesses. As Parkinson's is not a curable disease, all treatments are focused on slowing decline and improving quality of life, and are therefore palliative in nature. Palliative care should be involved earlier, rather than later, in the disease course. Palliative care specialists can help with physical symptoms, emotional factors such as loss of function and jobs, depression, fear, and existential concerns. Along with offering emotional support to both the affected person and family, palliative care serves an important role in addressing goals of care. People with PD may have many difficult decisions to make as the disease progresses, such as wishes for feeding tube, non-invasive ventilation, noninvasive ventilator or Tracheotomy, tracheostomy, wishes for or against cardiopulmonary resuscitation, and when to use hospice care. Palliative-care team members can help answer questions and guide people with PD on these complex and emotional topics to help them make the best decision based on their own values. Muscles and nerves that control the digestive process may be affected by PD, resulting in constipation and gastroparesis (food remaining in the stomach for a longer period than normal). A balanced diet, based on periodical nutritional assessments, is recommended, and should be designed to avoid weight loss or gain and minimize the consequences of gastrointestinal dysfunction. As the disease advances, swallowing difficulties (dysphagia) may appear. In such cases, using thickening agents for liquid intake and an upright posture when eating may be useful; both measures reduce the risk of choking. Gastrostomy to deliver food directly into the stomach is possible in severe cases. Levodopa and proteins use the same transportation system in the intestine and the blood–brain barrier, thereby competing for access. Taking them together results in reduced effectiveness of the drug. Therefore, when levodopa is introduced, excessive protein consumption is discouraged, and a well-balanced Mediterranean diet is recommended. In advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons. 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.


Prognosis

PD invariably progresses with time. A severity rating method known as the Unified Parkinson's disease rating scale (UPDRS) is the most commonly used metric for a clinical study. A modified version known as the MDS-UPDRS is also sometimes used. An older scaling method known as the Hoehn and Yahr scale (originally published in 1967), and a similar scale known as the Modified Hoehn and Yahr scale, have also been commonly used. The Hoehn and Yahr scale defines five basic stages of progression. 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 10 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. Predicting what course the disease will take for a given individual is difficult. 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 nonmotor 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 levodopa-induced 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 is a statistical measure of the average time an organism is expected to live, based on the year of its birth, its current age, and other demographic Demography (from prefix ''demo-'' from Ancient Greek Ancien ...

life expectancy
of people with PD is reduced. Standardized mortality ratio, Mortality ratios 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 factors. A disease pattern mainly characterized by tremor as opposed to rigidity, though, predicts an improved survival. Death from aspiration pneumonia is twice as common in individuals with PD as in the healthy population. In 2016, PD resulted in about 211,000 deaths globally, an increase of 161% since 1990. The overall death rate increased by 19% to 1.81 per 100,000 people during that time.


Epidemiology

PD is the second most common neurodegeneration, neurodegenerative disorder after
Alzheimer's disease Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neuron A neuron or nerve cell is an membrane p ...
and affects approximately seven million people globally and one million people in the United States. The prevalence, proportion in a population at a given time is about 0.3% in industrialized countries. PD is more common in the elderly and rates rise 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 PD, begin between the ages of 20 and 50. Males are more often affected than females at a ratio of around 3:2. PD may be less prevalent in those of African and Asian ancestry, although this finding is disputed. The incidence (epidemiology), number of new cases per year of PD is between 8 and 18 per 100,000 person–years. The age-adjusted rate of Parkinson's disease in Estonia is 28.0/100,000 person years. The Estonian rate has been stable between 2000 and 2019. The incidence of Parkinson's disease has increased in China. It is estimated that China will have nearly half of the Parkinson's disease population in the world in 2030. By the year 2040 the number of patients is expected to grow to approximately 14 million people; this growth has been referred to as the ''Parkinson's pandemic.''


History

Several early sources, including an Ancient Egypt, Egyptian papyrus, an ayurveda, Ayurvedic medical treatise, the Bible, and Galen's writings, describe symptoms resembling those of PD.. The article mistakenly refers to Job 34:19 instead of Job 33:19. 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 Franciscus Sylvius, Sylvius, Hieronymus David Gaubius, Gaubius, John Hunter (surgeon), Hunter and Auguste François Chomel, Chomel. In 1817, an English doctor,
James Parkinson James Parkinson Geological Society of London, FGS (11 April 175521 December 1824) was an English surgeon, apothecary, geologist, palaeontologist and political Activism, activist. He is best known for his 1817 work ''An Essay on the Shaking Palsy' ...

James Parkinson
, 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 Armand Trousseau, Trousseau, William Gowers (neurologist), Gowers, Samuel Alexander Kinnier Wilson, Kinnier Wilson and Wilhelm Heinrich Erb, Erb, and most notably Jean-Martin Charcot, 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 described microscopic particles in affected brains, later named Lewy bodies. In 1919, Konstantin Tretiakoff reported that the substantia nigra was the main cerebral structure affected, but this finding was not widely accepted until it was confirmed by further studies published by Rolf Hassler in 1938. The underlying biochemical changes in the brain were identified in the 1950s, due largely to the work of Arvid Carlsson on the neurotransmitter dopamine and Oleh Hornykiewicz on its role on PD. In 1997, alpha-synuclein was found to be the main component of Lewy bodies by Maria Grazia Spillantini, Spillantini, John Q. Trojanowski, Trojanowski, Michel Goedert, Goedert and others. 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 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 (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator (sometimes referred to as a "brain pacemaker"), which sends electrical impulses, through implanted electrode An elect ...

deep brain stimulation
introduced by Alim Louis Benabid and colleagues at Grenoble, France, emerged as a possible treatment.


Society and culture


Cost

The costs of PD to society are high, but precise calculations are difficult due to methodological issues in research and differences between countries. The annual cost in the UK is estimated to be between £49 million and £3.3 billion, while the cost per affected person per year in the U.S. is probably around $10,000 and the total burden around $23 billion. The largest share of direct cost comes from inpatient care and nursing homes, while the share coming from medication 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 of those with the disease and their caregivers.


Advocacy

The birthday of James Parkinson, 11 April, has been designated as World Parkinson's Day. A red tulip was chosen by international organizations as the symbol of the disease in 2005; it represents the 'James Parkinson' tulip cultivar, registered in 1981 by a Dutch horticulturalist. Advocacy organizations include the National Parkinson Foundation, which has provided more than $180 million in care, research, and support services since 1982, Parkinson's Disease Foundation, which has distributed more than $115 million for research and nearly $50 million for education and advocacy programs since its founding in 1957 by William Black; the American Parkinson Disease Association, founded in 1961; and the European Parkinson's Disease Association, founded in 1992.


Notable cases

Actor
Michael J. Fox Michael Andrew Fox (born June 9, 1961), known professionally as Michael J. Fox, is a Canadian-American Canadian Americans is a term that can be applied to American citizens Citizenship is the Status (law), status of a person recognize ...
has PD and has greatly increased the public awareness of the disease. After diagnosis, Fox embraced his Parkinson's in television roles, sometimes acting without medication, to further illustrate the effects of the condition. He has written two autobiographies in which his fight against the disease plays a major role, and appeared before the United States Congress without medication to illustrate the effects of the disease. The Michael J. Fox Foundation aims to develop a cure for Parkinson's disease. Fox received an Honorary degree, honorary doctorate in medicine from Karolinska Institutet for his contributions to research in Parkinson's disease. Professional cyclist and Olympic medalist
Davis Phinney Davis Phinney (born July 10, 1959) is a retired professional road bicycle racer A road is a thoroughfare, route, or way on land between two Location (geography), places that has been Pavement (material), paved or otherwise improved to allow tr ...
, who was diagnosed with young-onset Parkinson's at age 40, started the Davis Phinney Foundation in 2004 to support PD research, focusing on quality of life for people with the disease. Boxer
Muhammad Ali Muhammad Ali (; born Cassius Marcellus Clay Jr.; January 17, 1942 – June 3, 2016) was an American professional boxer, activist, entertainer, poet and philanthropist. Nicknamed The Greatest, he is widely regarded as one of the most significa ...

Muhammad Ali
showed signs of PD when he was 38, but was not diagnosed until he was 42, and has been called the "world's most famous Parkinson's patient". Whether he had PD or Dementia pugilistica, parkinsonism related to boxing is unresolved. At the time of his suicide in 2014, Robin Williams, the American actor and comedian, had been diagnosed with PD. According to his widow, his autopsy found diffuse Lewy body disease, while the autopsy used the term ''diffuse Lewy body dementia''. Dennis Dickson, a spokesperson for the Lewy Body Dementia Association, clarified the distinction by stating that ''diffuse Lewy body dementia'' is more commonly called ''diffuse Lewy body disease'' and refers to the underlying disease process. Ian G. McKeith, professor and researcher of Lewy body dementias, commented that Williams' symptoms and autopsy findings were explained by
dementia with Lewy bodies Dementia with Lewy bodies (DLB) is a type of dementia Dementia manifests as a set of related symptoms, which usually surface when the brain is damaged by injury or disease. The symptoms Signs and symptoms are the observed or detectable s ...
. The televsion preenter and authorJeremy Paxman has described his PD symptoms as mild Shan Nicholas of Parkinson's UK has said, "Previously, Jeremy pledged to donate his brain to the Parkinson's UK Brain Bank which will, one day, help scientists uncover the discoveries that will lead to better treatments and a cure for Parkinson's."


Research

No disease-modifying drugs (drugs that target the causes or damage) are approved for Parkinson's, so this is a major focus of Parkinson's research. Active research directions include the search for new animal models of the disease and studies of the potential usefulness of gene therapy, stem cell transplants, and neuroprotective agents. To aid in earlier diagnosis, research criteria for identifying Prodrome, prodromal biomarker (medicine), biomarkers of the disease have been established.


Animal models

PD is not known to occur naturally in any species other than humans, although animal models that show some features of the disease are used in research. The appearance of parkinsonism in the early 1980s in a group of drug addicts who consumed a contaminated batch of the synthetic opiate Desmethylprodine, MPPP led to the discovery of the chemical MPTP as an agent that causes parkinsonism in nonhuman primates and humans. Other predominant toxin-based models employ the insecticide rotenone, the herbicide paraquat, and the fungicide maneb. Models based on toxins are most commonly used in primates. Transgene, Transgenic rodent models that replicate various aspects of PD have been developed. The use of neurotoxin oxidopamine, 6-hydroxydopamine creates a model of PD in rats by targeting and destroying dopaminergic neurons in the nigrostriatal pathway when injected into the substantia nigra.


Gene therapy

Gene therapy typically involves the use of a noninfectious virus (i.e., a viral vector such as the adeno-associated virus) to shuttle genetic material into a part of the brain. Several approaches have been tried. These approaches have involved the expression of growth factors to try to prevent damage (Neurturin – a GDNF family of ligands, GDNF-family growth factor), and enzymes such as glutamic acid decarboxylase (Glutamate decarboxylase, GAD – the enzyme that produces Gamma-Aminobutyric acid, GABA), tyrosine hydroxylase (the enzyme that produces L-DOPA) and Catechol-O-methyltransferase, catechol-O-methyl transferase (COMT – the enzyme that converts L-DOPA to dopamine). There have been no reported safety concerns, but the approaches have largely failed in phase 2 clinical trials. The delivery of GAD showed promise in phase 2 trials in 2011, but whilst effective at improving motor function, was inferior to DBS. Follow-up studies in the same cohort have suggested persistent improvement. There have been phase 1 clinical trials in recent years that have shown success. In a phase 1 trial sponsored by Genzyme/Voyager, the gene encoding for aromatic amino acid decarboxylase (AADC) was delivered to the putamen in the brains of people with PD. AADC is an enzyme which is key in the transformation of levodopa to dopamine. The decreasing levels of this AADC enzyme in PD could be linked with the loss of levodopa’s efficiency with time. Thus, increase in AADC expression through gene therapy could result in more effective levodopa treatment. The outcomes of this phase 1 trial were promising in that the people who received the therapy showed modest improvement.


Neuroprotective treatments

Investigations on neuroprotection are at the forefront of PD research. Several molecules have been proposed as potential treatments. However, none of them has been conclusively demonstrated to reduce degeneration. Agents currently under investigation include, Glutamic acid, antiglutamatergics, monoamine oxidase inhibitors (selegiline, rasagiline), Mitochondrion, promitochondrials (coenzyme Q10, creatine), calcium channel blockers (isradipine) and growth factors (Glial cell line-derived neurotrophic factor, GDNF). Reducing
alpha-synuclein Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, while smaller a ...
pathology is a major focus of preclinical research. A vaccine that primes the human immune system to destroy
alpha-synuclein Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, while smaller a ...
, PD01A (developed by Austrian company, Affiris), entered clinical trials and a phase 1 report in 2020 suggested safety and tolerability. In 2018, an antibody, PRX002/RG7935, showed preliminary safety evidence in stage I trials supporting continuation to stage II trials.


Cell-based therapies

Since early in the 1980s, fetus, fetal, pig, porcine, Common carotid artery, carotid or retinal tissues have been used in Cell-based therapies for Parkinson's disease, 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. These sources of tissues have been largely replaced by induced pluripotent stem cell derived dopaminergic neurons, as this is thought to represent a more feasible source of tissue. Initial evidence showed Mesencephalon, mesencephalic dopamine-producing cell transplants being beneficial, but Double-blind#Double-blind trials, double-blind trials to date have not determined a long-term benefit. An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to Tardive dyskinesia, dyskinesia. In 2020, a first in human clinical trial reported the transplantation of induced pluripotent stem cells into the brain of a person suffering from PD.


Other

Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias. Its usefulness in PD is an open research topic. Several nutrients have been proposed as possible treatments; however there is no evidence that vitamins or food additives improve symptoms. No evidence substantiates that acupuncture and practice of Qigong, or T'ai chi ch'uan, T'ai chi, have any effect on the course of the disease or symptoms. The role of the gut–brain axis and the gut flora in PD became a topic of study in the 2010s, starting with work in germ-free transgenic mice, in which fecal transplants from people with PD had worse outcomes. Some studies in humans have shown a correlation between patterns of dysbiosis in the gut flora in the people with PD, and these patterns, along with a measure of severity of constipation, could diagnose PD with a 90% specificity but only a 67% sensitivity. As of 2017, some scientists hypothesized that changes in the gut flora might be an early site of PD pathology, or might be part of the pathology. Evidence indicates that gut microbiota can produce lipopolysaccharide that interferes with the normal function of α-synuclein. Ventures have been undertaken to explore antagonists of adenosine receptors (specifically Adenosine A2A receptor, A2A) as an avenue for novel drugs for Parkinson's. Of these, istradefylline has emerged as the most successful medication and was approved for medical use in the United States in 2019. It is approved as an add-on treatment to the levodopa/carbidopa regime.


References


External links

*
Parkinson's Disease: Hope Through Research (National Institute of Neurological Disorders and Stroke)

World Parkinson Disease Association

PDGENE – Database for Parkinson's Disease genetic association studies
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