Four motor symptoms are considered cardinal signs in PD: slowness of movement (bradykinesia), tremor, rigidity, and postural instability.[1] Typical for PD is an initial asymmetric distribution of these symptoms, where in the course of the disease, a gradual progression to bilateral symptoms develops, although some asymmetry usually persists. Other motor symptoms include gait and posture disturbances such as decreased arm swing, a forward-flexed posture, and the use of small steps when walking; speech and swallowing disturbances; and other symptoms such as a mask-like facial expression or small handwriting are examples of the range of common motor problems that can appear.[1]Cardinal signs[edit]Four motor signs are considered cardinal in PD: tremor, rigidity, bradykinesia, and postural instability (also referred to as parkinsonism).[1]
Tremor is the most apparent and well-known sign.[1] It is also the most common; though around 30% of individuals with PD do not have tremor at disease onset, most develop it as the disease progresses.[1] It is usually a rest tremor, maximal when the limb is at rest and disappearing with voluntary movement and sleep.[1] It affects to a greater extent the most distal part of the limb, and at onset typically appears in only a single arm or leg, becoming bilateral later during the course of the disease.[1] Frequency of PD tremor is between 4 and 6 hertz (cycles per second). It is a pronation-supination tremor that is described as "pill-rolling", that is the index finger of the hand tends to get into contact with the thumb, and they perform a circular movement together.[1] [2] Such term was given due to the similarity of the movement in PD patients with the former pharmaceutical technique of manually making pills.[2] PD tremor is not improved with alcohol intake, as opposed to essential tremor.[1]
Rigidity is characterized by an increased muscle tone (an excessive and continuous contraction of the muscles) which produces stiffness and resistance to movement in joints.[1] Rigidity may be associated with joint pain, with such pain being a frequent initial manifestation of the disease.[1] When limbs of the person with PD are passively moved by others, a "cogwheel rigidity" is commonly seen.[1] Cogwheel-like or ratchety jerks are characterized by the articulation moving as opposed to the normal fluid movement; when a muscle is externally tried to move, it resists at first, but with enough force, it is partially moved until it resists again, and only with further force, will it be moved.[1] [3] [4] The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity.[5]
Bradykinesia and akinesia: the former is slowness of movement, while the latter is the absence of it.[1] It is the most characteristic clinical feature of PD, and is associated with difficulties along the whole course of the movement process, from planning to initiation and finally execution of a movement.[1] The performance of sequential and simultaneous movements is also hindered.[1] Bradykinesia is the most disabling symptom in the early stages of the disease.[3] Initial manifestations of bradykinesia are problems when performing daily life tasks requiring fine motor control such as writing, sewing, or getting dressed.[1] Clinical evaluation is based in similar tasks consisting such as alternating movements between both hands or feet.[3] Bradykinesia is not equal for all movements or times. It is modified by the activity or emotional state of the subject to the point of some patients who are barely able to walk being capable of riding a bicycle.[1] Generally, patients have less difficulties when some sort of external cue is provided.[1] [6]
... immobile patients who become excited may be able to make quick movements such as catching a ball (or may be able to suddenly run if someone screams "fire"). This phenomenon (kinesia paradoxica) suggests that patients with PD have intact motor programmes, but have difficulties accessing them without an external trigger, such as a loud noise, marching music, or a visual cue requiring them to step over an obstacle.[1] Postural instability: In the late stages, postural instability is typical, which leads to impaired balance and frequent falls, and secondarily to bone fractures.[1] Instability is often absent in the initial stages, especially in younger people.[3] Up to 40% of the patients may experience falls and around 10% may have falls weekly, with the number of falls being related to the severity of PD. It is produced by a failure of postural reflexes, along other disease-related factors such as orthostatic hypotension or cognitive and sensory changes.[1]
Other motor symptoms[edit]



Drawing of a Parkinson's disease patient face showing hypomimia: Depiction appeared in Nouvelle iconographie de la Salpétrière, vol 1 (1888)



Example of writing by a patient with Parkinson's disease, possibly showing micrographia in addition to other abnormal characteristics. published by Jean-Martin Charcot in 1879: Text accompanying image stated, "The strokes forming the letters are very irregular and sinuous, whilst the irregularities and sinuosities are of a very limited width. On a careful examination of this specimen of writing, it will be perceived that the down-strokes are all, with the exception of the first letter, made with comparative firmness and are, in fact, nearly normal — the finer up-strokes, on the contrary, are all tremulous in appearance, and it is to the unsteadiness of these lines that the peculiar character of the writing here is principally due."Other motor symptoms include:Gait and posture disturbances:Shuffling gait[1] is characterized by short steps, with feet barely leaving the ground. Small obstacles tend to cause the patient to trip.
Decreased arm-swing[1]
Turning 'en bloc, rather than the usual twisting of the neck and trunk and pivoting on the toes, is when PD patients keep their necks and trunks rigid, requiring multiple small steps to accomplish a turn.
Camptocormia [1] is a stooped, forward-flexed posture. In severe forms, the head and upper shoulders may be bent at a right angle relative to the trunk.[7]
Festination [1] is a combination of stooped posture, imbalance, and short steps. It leads to a gait that gets progressively faster and faster, often ending in a fall.
Gait freezing, also called motor blocks, is a manifestation of akinesia.[1] Gait freezing is characterized by a sudden inability to move the lower extremities which usually lasts less than 10 seconds.[1] It may worsen in tight, cluttered spaces, when attempting to initiate gait or turning around, or when approaching a destination.[1] Freezing improves with treatment and also with behavioral techniques such as marching to command or following a given rhythm.[1]
Dystonia [1] is abnormal, sustained, sometimes painful twisting muscle contractions, often affecting the foot and ankle (mainly toe flexion and foot inversion), which often interferes with gait.
Scoliosis is abnormal curvature of the spine.[1]

Speech and swallowing disturbances:Hypophonia [1] (soft speech).
Monotonic speech - quality tends to be soft, hoarse, and monotonous.[1]
Festinating speech - excessively rapid, soft, poorly intelligible speech.
Drooling is most likely caused by a weak, infrequent swallow.[1]
Dysphagia is an impaired ability to swallow, which in the case of PD is probably related to an inability to initiate the swallowing reflex or by a too long laryngeal or oesophageal movement.[1] It can lead to aspiration pneumonia.
Dysarthria is a form of speech disorder.[1]

Other motor symptoms and signs:Fatigue
Hypomimia [1] (a mask-like face).
Difficulty rolling in bed or rising from a seated position.[1]
Micrographia [1] (small, cramped handwriting).
Impaired fine-motor dexterity and motor coordination [1]
Impaired gross-motor coordination.
Akathisia (an unpleasant desire to move, often related to medication).
Reemergence of primitive reflexes.[1]
Glabellar reflex

Neuropsychiatric[edit]
See also: Neuronal death in Parkinson's DiseaseExample of reported prevalences of mood problems in PD patients with dementia[1] [8]Mood problemPrevalenceDepression 58%Apathy 54%Anxiety 49%Parkinson's disease causes neuropsychiatric disturbances, which mainly include cognitive disorders, mood disorders, and behavior problems, and can be as disabling as motor symptoms.[1]Since L-Dopa, the widely used drug in Parkinson's disease treatment, is decarboxylated by aromatic L-amino acid decarboxylase (AADC), which is found in both dopaminergic and serotonergic neurons, it is possible for serotonergic neurons to convert L-Dopa into dopamine and generate excessive neuronal death by creating reactive oxygen species and quinoproteins. The association of serotonin with mood and cognition may explain some of the side-effects observed in patients treated with L-Dopa due to serotonin deficit.[9] [10]In most cases, motor symptoms predominate at early PD stages, while cognitive disturbances (such as mild cognitive impairment or dementia) emerge later.[11] The onset of parkinsonism in PD relative to dementia is used as an arbitrary criterion to clinically distinguish Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) using a ‘one-year rule’.[11] Dementia onset within 12-months of or at the same time as motor dysfunctions qualified as DLB, whereas in PDD, parkinsonism had to precede dementia by at least one year.[11]Cognitive disturbances occur even in the initial stages of the disease in some cases.[12] A very high proportion of sufferers have mild cognitive impairment as the disease advances.[1] Most common deficits in nondemented patients are:Executive dysfunction, which translates into impaired set shifting, poor problem solving, and fluctuations in attention among other difficulties[12]
Slowed cognitive speed (bradyphrenia)[12]
Memory problems can occur, specifically in recalling learned information, with an important improvement with cues. Recognition memory is less impaired than free recall, pointing towards a retrieving more than to an encoding problem.[12]
Regarding language, patients are found to have problems in verbal fluency tests.[12]
Visuospatial skills difficulties, which are seen when the person with PD is for example asked to perform tests of face perception and perception of line orientation.[12]
Deficits tend to aggravate with time, developing in many cases into dementia. A person with PD has a six-fold increased risk of suffering it,[1] and the overall rate in people with the disease is around 30%.[12] Moreover, prevalence of dementia increases in relation to disease duration, going up to 80%.[12] Dementia has been associated with a reduced quality of life in disease sufferers and caregivers, increased mortality, and a higher probability of moving to a nursing home.[12]Cognitive problems and dementia are usually accompanied by behavior and mood alterations, although these kinds of changes are also more common in those patients without cognitive impairment than in the general population. Most frequent mood difficulties include:[1] Depression [1] is well recognized in PD, having been identified as "melancholia" by James Parkinson in his original report of the disease in 1817. Estimated prevalence rates of depression vary widely according to the population sampled and methodology used, although depressive symptoms, irrespective of classically defined DSM criteria for depression, are present in 35% of patients[13] There is an increased risk for any individual with depression to go on to develop Parkinson's disease at a later date.[14] [15] [16] It is increasingly thought to be a consequence of the disease rather than an emotional reaction to disability, although ample evidence shows that the relationship between depression and PD is bidirectional.[17] [18] General risk factors for depression are actually stronger markers for depression in PD patients than PD specific factors.[19] Since Parkinson's affects many areas of the brain that control mood (specifically the frontal lobe as well as those areas that produce serotonin, norepinephrine and dopamine), depression may result.[20] Depression is one of the most common neuropsychiatric conditions found in patients who have PD, and it is associated with more rapid progression of physical symptoms and a greater decline in cognitive skills. Depression in patients with PD was found to be more predictive of overall disability than was the motor disability from the PD. An interesting finding is that although a high rate of depression is seen in patients with PD, the incidence of suicide is lower in this group of patients.[21] Many of the symptoms of PD may overlap with those of depression, making diagnosis a difficult issue.[22]
Apathy [1]
Anxiety [1] is seen; 70% of individuals with PD diagnosed with pre-existing depression go on to develop anxiety. About 90% of PD patients with pre-existing anxiety subsequently develop depression, apathy, or abulia.
Obsessive–compulsive behaviors (also known as Impulse-control disorders) such as craving, binge eating, hypersexuality, pathological gambling, punding, or others, can also appear in PD, and have been related to a dopamine dysregulation syndrome associated with the medications for the disease.[1] Psychotic symptoms are common in PD, generally associated with dopamine therapy. Symptoms of psychosis, or impaired reality testing, are either hallucinations, typically visual, less commonly auditory, and rarely in other domains including tactile, gustatory, or olfactory, or delusions, that is, irrational beliefs. Hallucinations are generally stereotyped and without emotional content. Initially, patients usually have insight so that the hallucinations are benign in terms of their immediate impact, but have poor prognostic implications, with increased risk of dementia, worsened psychotic symptoms, and mortality. Delusions occur in about 5-10% of treated patients, and are considerably more disruptive, being paranoid in nature, of spousal infidelity or family abandonment. Psychosis is an independent risk factor for nursing-home placement.[23]Hallucinations can occur in parkinsonian syndromes for a variety of reasons. An overlap exists between PD and dementia with Lewy bodies, so that where Lewy bodies are present in the visual cortex, hallucinations may result. Hallucinations can also be brought about by excessive dopaminergic stimulation. Most hallucinations are visual in nature, often formed as familiar people or animals, and are generally not threatening in nature. Some patients find them comforting; however, their caregivers often find this part of the disease most disturbing, and the occurrence of hallucinations is a major risk factor for hospitalisation. Treatment options consist of modifying the dosage of dopaminergic drugs taken each day, adding an antipsychotic drug such as quetiapine, or offering caregivers a psychosocial intervention to help them cope with the hallucinations.Sleep[edit]



Rapid eye movement sleep is altered in PD as opposed to the shown EEG polysomnographic record representing normal REMSleep problems can be worsened by medications for PD, but they are a core feature of the disease.[1] Sleep dysfunction in PD has significant negative impacts on both patient and carer quality of life.[24] Some common symptoms are:Excessive daytime somnolence [1]
Insomnia, characterized mostly by sleep fragmentation[1]
Disturbances in rapid eye movement sleep: disturbingly vivid dreams, and rapid eye movement behavior disorder, characterized by acting out of dream content:[1] It appears in a third of the patients and it is a risk factor for PD in the overall population.[1]
Perception[edit]Impaired proprioception (the awareness of bodily position in three-dimensional space)
Reduction or loss of sense of smell (hyposmia or anosmia)[1] may be an early marker of the disease.[1]
Paresthesias [1]
Autonomic[edit]Orthostatic hypotension [1] leading to dizziness and fainting
Oily skin[25]
Urinary incontinence [1] (typically in later disease progression) and nocturia (getting up in the night to pass urine)
Altered sexual function[1] is characterized by profound impairment of sexual arousal, behavior, orgasm, and drive, and is found in mid- and late PD.
Excessive sweating [1]
Gastrointestinal[edit]Parkinson's Disease causes constipation and gastric dysmotility that is severe enough to endanger comfort and even health.[26] A factor in this is the appearance of Lewy bodies and Lewy neurites even before these affect the functioning of the substantia nigra in the neurons in the enteric nervous system that control gut functions.[27]Neuro-ophthalmological[edit]PD is related to different ophthalmological abnormalities produced by the neurological changes.[1] [28] Among them are:Decreased blink rate[1]
Irritation of the eye surface[1]
Alteration in the tear film[1]
Visual hallucinations[1]
Decreased eye convergence [1]
Blepharospasm [1]
Abnormalities in ocular pursuit, ocular fixation[29] and saccadic movements [1]
Difficulties opening the eyelids[1] This can have particular relevance when driving. People with Parkinson's have been shown to be less accurate in spotting landmarks and roadsigns whilst driving.[30]
Limitations in upward gaze[1]
Blurred vision [28]
Diplopia (double vision), produced by a reduced eye convergence.[28]
References[edit]
^ Jump up to:a  b  c  d  e  f  g  h  i  j  k  l  m  n  o  p  q  r  s  t  u  v  w  x  y  z  aa  ab  ac  ad  ae  af  ag  ah  ai  aj  ak  al  am  an  ao  ap  aq  ar  as  at  au  av  aw  ax  ay  az  ba  bb  bc  bd  be  bf  bg  bh  bi  bj  bk  bl  bm  bn  bo  bp  bq  br  bs  bt  bu  bv  bw  Jankovic J (April 2008). "Parkinson's disease: clinical features and diagnosis". J. Neurol. Neurosurg. Psychiatry. 79 (4): 368–76. doi:10.1136/jnnp.2007.131045. PMID 18344392.
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Many risk factors have been proposed, sometimes in relation to theories concerning possible mechanisms of the disease; however, none has been proven conclusively.[54] The most frequently replicated relationships are an increased risk in those exposed to pesticides, and a reduced risk in smokers.[54] [55] A possible link exists between PD and  Helicobacter pylori infection that can prevent the absorption of some drugs, including levodopa.[56] [57]Genetic[edit]



Parkin crystal structureResearch indicates that PD is the product of a complex interaction of genetic and environmental factors.[5] Around 15% of individuals with PD have a first-degree relative who has the disease,[17] 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.[58] [59] 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.[58] At least 11 autosomal dominant and 9 autosomal recessive gene mutations have been implicated in the development of PD. The autosomal dominant genes include SNCA , PARK3, UCHL1 ,  LRRK2, GIGYF2 , HTRA2 , EIF4G1 ,  TMEM230,  CHCHD2,  RIC3, and  VPS35. Autosomal recessive genes include  PRKN, PINK1, PARK7, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, and  VPS13C. Some genes are X-linked or have unknown inheritance pattern; those include  PARK10, PARK12, and  PARK16. A 22q11 deletion is also known to be associated with PD.[60] [59] An autosomal dominant form has been associated with mutations in the LRP10 gene.[13] [61]About 5% of people with PD have mutations in the  GBA1 gene.[62] 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, is the main component of the Lewy bodies that accumulate in the brains of people with PD.[58] Alpha-synuclein activates ataxia telangiectasia mutated, a major DNA damage-repair signaling kinase.[63] 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.[63]Mutations in some genes, including SNCA, LRRK2, and GBA, have been found to be risk factors for sporadic (nonfamilial) PD.[58] 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.[64] [58] A mutation in GBA presents the greatest genetic risk of developing Parkinsons disease.[65]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 disorders that reduce the ability of cells to break down alpha-synuclein.[66]Non-genetic[edit]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.[47] Some toxins can cause parkinsonism, including manganese and carbon disulfide.[67] [68] [69] [70]Medical drugs implicated in cases of parkinsonism. Drug-induced parkinsonism is normally reversible by stopping the offending agent,[68] such as phenothiazines (chlorpromazine, promazine, etc.); butyrophenones (haloperidol, benperidol, etc.); metoclopramide and Tetrabenazine. 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.[68] [71] [72]Low concentrations of urate in the blood is associated with an increased risk of PD.[73]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 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.[17] [74] 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 dementia. The relationship between PD and DLB is complex and incompletely understood.[75] They may represent parts of a continuum, with variable distinguishing clinical and pathological features, or they may prove to be separate diseases.[75]Vascular parkinsonism is the phenomenon of the presence of Parkinson's disease symptoms combined with findings of vascular events (such as a 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.[76] [68] [77]Pathophysiology[edit]



A Lewy body (stained brown) in a brain cell of the substantia nigra in Parkinson's disease: The brown colour is positive immunohistochemistry staining for alpha-synuclein.
Main article: Pathophysiology of Parkinson's diseaseThe main pathological characteristics of PD are cell death in the brain's basal ganglia (affecting up to 70% of the dopamine-secreting neurons in the substantia nigra pars compacta by the end of life).[64] In Parkinson's disease, alpha-synuclein becomes misfolded and clump together with other alpha-synuclein. Cells are unable to remove these clumps, and the alpha-synuclein becomes cytotoxic, damaging the cells.[12] [78] 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 glial cells) and a significant increase in the number of microglia (another type of glial cell) in the substantia nigra.[79] 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.[15]





Schematic initial progression of Lewy body deposits in the first stages of PD, as proposed by Braak and colleagues
Localization of the area of significant brain volume reduction in initial PD compared with a group of participants without the disease in a neuroimaging study, which concluded that brainstem damage may be the first identifiable stage of PD neuropathology [80]
Five major pathways in the brain connect other brain areas with the basal ganglia. These are known as the motor, oculomotor, associative, limbic, and orbitofrontal circuits, with names indicating the main projection area of each circuit.[81] 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.[81] Scientifically, the motor circuit has been examined the most intensively.[81]



An illustration of the dopamine pathways throughout the brain.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.[81] In this model, the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus, the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output.[81] 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.[81]Brain cell death[edit]Brain cells could be lost by several proposed mechanisms.[82] 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 inclusions called Lewy bodies.[64] [83] 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 and basal forebrain, and finally, the neocortex.[64] 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 neurites may actually be the toxic forms of the protein.[82] [83] 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.[79]Other cell-death mechanisms include proteasomal and lysosomal systems dysfunction and reduced mitochondrial activity.[82] 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.[84]

A physician initially assesses for PD with a careful medical history and neurological examination.[32] 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.[32] [85]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.[15] [85] Parkinson-plus syndromes, such as progressive supranuclear palsy and multiple system atrophy, must also be considered and 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).[32] 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.[86]Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process, especially in the early stages of the disease. The most widely known criteria come from the UK 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.[87] Assessment of sudomotor function through electrochemical skin conductance can be helpful in diagnosing dysautonomia.[88]When PD diagnoses are checked by autopsy, movement disorders experts are found on average to be 79.6% accurate at initial assessment and 83.9% accurate after they have refined their diagnoses at follow-up examinations. When clinical diagnoses performed mainly by nonexperts are checked by autopsy, the average accuracy is 73.8%. Overall, 80.6% of PD diagnoses are accurate, and 82.7% of diagnoses using the Brain Bank criteria are accurate.[89]Imaging[edit]Computed tomography (CT) scans of people with PD usually appear normal.[90] Magnetic resonance imaging has become more accurate in diagnosis of the disease over time, specifically through iron-sensitive 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.[91] In a meta-analysis, absence of this pattern was highly sensitive and specific for the disease.[92] A meta-analysis found that neuromelanin-MRI can discriminate individuals with Parkinson's from healthy subjects.[93] Diffusion MRI has shown potential in distinguishing between PD and Parkinson-plus syndromes, though its diagnostic value is still under investigation.[90] CT and MRI are also used to rule out other diseases that can be secondary causes of parkinsonism, most commonly encephalitis and chronic ischemic insults, as well as less frequent entities such as basal ganglia tumors and hydrocephalus.[90]The 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.[94] 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.[90] In the United States, DaTSCANs are only FDA approved to distinguish PD or Parkinsonian syndromes from essential tremor.[95]Iodine-123-meta-iodobenzylguanidine myocardial scintigraphy can help find denervation of the muscles around the heart, which can support a PD diagnosis.[15]Differential diagnosis[edit]Secondary parkinsonism – The multiple causes of parkinsonism can be differentiated between with careful history, physical examination, and appropriate imaging.[68] [15] [96] This topic is further discussed in the causes section here.



Hot Cross Bun sign that is commonly found in MRI of Multiple System Atrophy.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. 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.[97] [96] Some key features between them:[68] [96]
Corticobasal syndrome - levodopa-resistance, myoclonus, dystonia, corticosensory loss, apraxia, and non-fluent aphasia
Multiple system atrophy – levodopa resistance, rapidly progressive, autonomic failure, stridor, present 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.[96] [68]

No cure for Parkinson's disease is known. Medications, surgery, and 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.[101] The main families of drugs useful for treating motor symptoms are levodopa always combined with a dopa decarboxylase inhibitor and sometimes also with a COMT inhibitor, dopamine agonists, and MAO-B inhibitors. The stage of the disease and the age at disease onset determine which group is most useful.[101] Braak staging of PD uses six stages that can identify early, middle, and late stages.[102] 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.[102]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.[103] 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.[104]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.[103] When oral medications are not enough to control symptoms, surgery, deep brain stimulation, subcutaneous waking-day apomorphine infusion, and enteral dopa pumps may be useful.[105] 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.[105] In the final stages of the disease, palliative care is provided to improve a person's quality of life.[106]A 2020 Cochrane review found no certain evidence that cognitive training is beneficial for people with Parkinson's disease, dementia or mild cognitive impairment.[107] The findings are based on low certainty evidence of seven studies.

Levodopa[edit]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 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.[103]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.[108] Carbidopa and benserazide are 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.[109]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.[103] 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).[103] Using lower doses of levodopa may reduce the risk and severity of these levodopa-induced complications.[110] 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.[103] Most people with PD eventually need levodopa and later develop levodopa-induced fluctuations and dyskinesias.[103] Controlled-release (CR) versions of levodopa are available. Older CR levodopa preparations have poor and unreliable 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.Inbrija is an inhaled form of carbidopa-levodopa used when oral medications are not effective.[ better source needed][111]COMT inhibitors[edit]



COMT metabolizes levodopa to 3-O-methyldopa. COMT inhibitors help stop this reaction, allowing for more levodopa to cross the blood-brain barrier and become dopamine where it is needed.[112]During the course of PD, affected people can experience a wearing off phenomenon, where they have a recurrence of symptoms after a dose of levodopa, but right before their next dose.[15] Catechol-O-methyltransferase (COMT) is a protein that degrades levodopa before it can cross the blood-brain barrier and these inhibitors allow for more levodopa to cross.[113] 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.[15]Three COMT inhibitors are available to treat adults with PD and end-of-dose motor fluctuations – opicapone, entacapone, and tolcapone.[15] Tolcapone has been available for several years, but its usefulness is limited by possible liver damage complications, so requires liver-function monitoring.[114] [68] [15] [113] Entacapone and opicapone have not been shown to cause significant alterations to liver function.[113] [115] [116] Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.[117] [68] [118] Opicapone is a once-daily COMT inhibitor.[119] [15]Dopamine agonists[edit]Several dopamine agonists that bind to dopamine receptors in the brain have similar effects to levodopa.[103] 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.[103] [120] 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.[17] 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.[17] Thus, dopamine agonists are the preferred initial treatment for younger-onset PD, and levodopa is preferred for older-onset PD.[17]Dopamine agonists produce significant, although usually mild, side effects, including drowsiness, hallucinations, insomnia, nausea, and constipation.[103] Sometimes, side effects appear even at a minimal clinically effective dose, leading the physician to search for a different drug.[103] Agonists have been related to impulse-control disorders (such as compulsive sexual activity, eating, gambling, and shopping) even more strongly than levodopa.[121] They tend to be more expensive than levodopa.[17] Apomorphine, a dopamine agonist, may be used to reduce off periods and dyskinesia in late PD.[103] It is administered only by intermittent injections or continuous subcutaneous infusions.[103] Since secondary effects such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be closely monitored.[103] 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.[122]MAO-B inhibitors[edit]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.[103] 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).[123] An initial study indicated that selegiline in combination with levodopa increased the risk of death, but this has been refuted.[124]Common side effects are nausea, dizziness, insomnia, sleepiness, and (in selegiline and rasagiline) orthostatic hypotension.[123] [15] 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.[123]Other drugs[edit]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.[103] [125] 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.[126] Examples are the use of quetiapine for psychosis, cholinesterase inhibitors for dementia, and modafinil for excessive daytime sleepiness.[126] [127] In 2016, pimavanserin was approved for the management of PD psychosis.[128] Doxepin and rasagline may reduce physical fatigue in PD.[129]Surgery[edit]



Placement of an electrode into the brain: The head is stabilised in a frame for stereotactic surgery.Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa, the number of operations has declined.[130] 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.[130] Surgery for PD can be divided in two main groups – lesional and deep brain stimulation (DBS). Target areas for DBS or lesions include the thalamus, globus pallidus, or subthalamic nucleus.[130] DBS involves the implantation of a medical device called a 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.[131] Other, less common surgical therapies involve intentional formation of lesions to suppress overactivity of specific subcortical areas. For example, pallidotomy involves surgical destruction of the globus pallidus to control dyskinesia.[130]Four areas of the brain have been treated with neural stimulators in PD.[132] 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.[133]Rehabilitation[edit]
Further information: Management of Parkinson's diseaseExercise programs are recommended in people with PD.[19] Some evidence shows that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality.[134] [135] Regular physical exercise with or without physical therapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.[135] 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.[136] Clinical exercises may be an effective intervention targeting overall well-being of individuals with Parkinson's. Improvement in motor function and depression may happen.[137]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.[138] 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).[139] 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.[140] 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.[141] Exercise may improve constipation.[18] If exercise reduces physical fatigue in PD remains unclear.[129] 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.[142]One of the most widely practiced treatments for speech disorders associated with PD is the Lee Silverman voice treatment (LSVT).[134] [143] Speech therapy and specifically LSVT may improve speech.[134] Occupational therapy (OT) aims to promote health and quality of life by helping people with the disease to participate in as many of their daily living activities as possible.[134] 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.[134] [144]Palliative care[edit]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.[145] 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.[146]Palliative care should be involved earlier, rather than later, in the disease course.[147] [148] Palliative care specialists can help with physical symptoms, emotional factors such as loss of function and jobs, depression, fear, and existential concerns.[147] [148] [149]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, noninvasive ventilator or tracheostomy, wishes for or against cardiopulmonary resuscitation, and when to use hospice care.[146] 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.[148] [150]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).[18] 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.[18] 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.[18]Levodopa and proteins use the same transportation system in the intestine and the blood–brain barrier, thereby competing for access.[18] Taking them together results in reduced effectiveness of the drug.[18] 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.[18] To minimize interaction with proteins, levodopa should be taken 30 minutes before meals.[18] At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.[18]