implicated in pd. pd patients have altered gut microbiota and colon problems years before motor issues arise. alpha-synuclein is produced in the gut and may migrate via the vagus nerve to the brainstem, and then to the substantia nigra. furthermore, the bacteria proteus mirabilis has been associated with higher levels of alpha-synuclein and an increase of motor symptoms in pd patients. further elucidation of the causal role of alpha-synuclein, the role of inflammation, the gut-brain axis, as well as an understanding of the individual differences in immune stress responses is needed to better understand the pathological development of pd. diagnosis physician's initial assessment is typically based on medical history and neurological examination. they access motor symptoms (bradykinesia, rest tremors, etc) using 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 diverge from pd, requiring that presentation is 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 be considered and ruled out appropriately to begin a 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 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 symptoms 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. 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 refining 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. imaging computed tomography (ct) scans of people with pd usually appear normal. 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. in a meta-analysis, absence of this pattern was highly sensitive and specific for the disease. a meta-analysis found that neuromelanin-mri can discriminate individuals with parkinson's from healthy subjects. diffusion mri has shown potential in distinguishing between pd and parkinson-plus syndromes, as well as between pd motor subtypes, though its diagnostic value is still under investigation. ct and mri are 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. 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. 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 nonspecific and can be seen with both pd and parkinson-plus disorders. in the united states, datscans are only fda approved to distinguish pd or parkinsonian syndromes from essential tremor. iodine-123-meta-iodobenzylguanidine myocardial scintigraphy can help locate denervation of the muscles of the heart which can support a pd diagnosis. differential diagnosis secondary parkinsonism – the multiple causes of parkinsonism can be differentiated through careful history, physical examination, and appropriate imaging. 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 exam (especially focused on the sequential onset of specific symptoms), progression of the disease, and response to treatment. some key symptoms: corticobasal syndrome – levodopa-resistance, myoclonus, dystonia, corticosensory loss, apraxia, and non-fluent aphasia dementia with lewy bodies – levodopa resistance, cognitive predominance before motor symptoms, and fluctuating cognitive symptoms, (visual hallucinations are common in this disease) essential tremor – this can at first look like parkinsonism, but has key differentiators. in essential tremor, the tremor gets worse with action (improves in pd), a lack of other symptoms is common in pd, and normal datscan is seen. 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 other conditions that can have similar presentations to pd include: arthritis creutzfeldt–jakob disease depression dystonia fragile x-associated tremor/ataxia syndrome frontotemporal dementia and parkinsonism linked to chromosome 17 huntington's disease 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 appears protective with a greater decrease in risk occurring with a larger intake of caffeinated beverages such as coffee. antioxidants, such as vitamins c and e, have been proposed to protect against the disease, but results of studies have been contradictory and no positive effect has been shown. the results regarding fat and fatty acids have been contradictory. use of nonsteroidal anti-inflammatory drugs (nsaids) and calcium channel blockers may be protective. a 2010 meta-analysis found that nsaids (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. as of 2019 meta-analyses have failed to confirm this link. multiple studies have demonstrated a link between the use of ibuprofen and a decreased risk of parkinson's development. management main article: management of parkinson's disease pharmacological treatment of parkinson's disease 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 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 levodopa always combined with a dopa decarboxylase inhibitor and 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. 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 and treatment should be prompt 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. 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 inadequate in controlling symptoms, surgery (deep brain stimulation or high-intensity focused ultrasound), subcutaneous waking-day apomorphine infusion, and enteral dopa pumps may be useful. late-stage pd presents 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. levodopa levodopa is usually the first drug of choice when treating parkinson's disease and has been the most widely used pd treatment since the 1980s. the motor symptoms of pd are the result of reduced dopamine production in the brain's basal ganglia. dopamine fails to cross the blood–brain barrier so it cannot be taken as a medicine to boost the brain's depleted levels of dopamine. a precursor of dopamine, levodopa, can pass through to the brain where it is readily converted to dopamine. administration of levodopa temporarily diminishes the motor symptoms of pd. 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 dopa decarboxylase inhibitors that fails to 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 and is availible combined with levodopa in the same pill. prlonged use of levodopa is associated with the development of complications, such as involuntary movements (dyskinesias) and fluctuations in the impact 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 increased pd symptoms (off state).: 1989 using lower doses of levodopa may reduce the risk and severity of these levodopa-induced complications. a former strategy, called "drug holidays", to reduce levodopa-related dyskinesia and fluctuations was to withdraw levodopa medication for some time which can bring on dangerous side effects such as neuroleptic malignant syndrome and is discouraged. most people with pd eventually need levodopa and later develop levodopa-induced fluctuations and dyskinesias. adverse effects of levodopa, including dyskinesias, mistakenly influence patients and providers to delay treatment which reduces potential for optimal results. levodopa by itself is available in oral (tablets and capsules), oral inhalation, and infusion form. inhaled levodopa can be used when oral levodopa therapy has reached a point where "off" periods have increased in length. comt inhibitors 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. during the course of pd, affected people can experience a wearing-off phenomenon, where a recurrence of symptoms occurs 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 and these inhibitors allow for more levodopa to cross. they are normally used in the management of later 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 used to treat adults with pd and end-of-dose motor fluctuations – opicapone, entacapone, and tolcapone. tolcapone has been available for but its usefulness is limited by possible liver damage complications requiring liver-function monitoring. entacapone and opicapone cause little alteration to liver function. licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa. opicapone is