to experience pleasure and are symptoms classically associated with depression, but differ in pd-affected people in treatment and mechanism. 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. anhedonia occurs in 5–75% of people with pd, depending on the study population assessed and overlap with apathy. impulse-control disorders, including pathological gambling, compulsive sexual behavior, binge eating, compulsive shopping, and reckless generosity, can be medication-related, particularly orally active dopamine agonists. the dopamine dysregulation syndrome – with wanting of medication contributing to overuse – is a rare complication of levodopa use. punding, complicated, repetitive, aimless, stereotyped behaviors, is another side effect of anti-parkinson medication. gastrointestinal gastrointestinal issues in parkinson's disease include constipation, impaired stomach emptying (gastric dysmotility), and excessive production of saliva can be severe enough to cause discomfort or endanger health. other upper gastrointestinal symptoms include swallowing impairment (oropharyngeal dysphagia) and small intestinal bacterial overgrowth. invidividuals with parkinson's have alpha-synuclein deposits in the digestive tract as well as the brain. constipation is one of the symptoms associated with an increased risk of pd and may precede diagnosis of pd. other sleep disorders occur with pd and can be worsened by medications. symptoms can manifest as daytime drowsiness (including sudden sleep attacks resembling narcolepsy), disturbances in rapid eye movement sleep, or insomnia. rem behavior disorder may begin years before the development of motor or cognitive elements of pd or dementia with lewy bodies. alterations in the autonomic nervous system can lead to orthostatic hypotension (low blood pressure on standing), oily skin, excessive sweating, urinary incontinence, and altered sexual function. changes in perception may include an impaired sense of smell, disturbed vision, pain, and paresthesia (tingling and numbness). these symptoms can occur years before diagnosis of the disease. causes main article: causes of parkinson's disease none of the proposed risk factors have been conclusively proven. 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 parkin crystal structure research indicates that pd results from a complex interaction between genetic and environmental factors. around 15% of diagnosed individuals have a first-degree relative who has the disease, and 5–10% have a mutation in genes. harboring one of these gene mutations may not lead to the disease; susceptibility factors put them at an increased risk, in combination with other factors, which affect age of onset, severity and progression. at least 11 autosomal dominant and nine 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 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 fewer 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 presentation, 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. alpha-synuclein, a protein encoded by snca gene mutations, is the main component of the lewy bodies that accumulate in the brains of people with pd. alpha-synuclein activates ataxia telangiectasia mutated, a major 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 pd. a mutation in gba presents the greatest genetic risk of developing parkinsons disease. parkinson-related genes are involved in the function of lysosomes, organelles that digest cellular waste products. lysosomal disorders that reduce the ability of cells to break down alpha-synuclein may cause pd. non-genetic exposure to pesticides and head injury have each been linked with pd, but the risks are low. not drinking caffeinated beverages is associated with small increases in risk. some toxins can cause parkinsonism, including manganese and carbon disulfide. medical drugs are implicated in 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. 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 urate in the blood are associated with an increased risk. other identifiable causes include infections and metabolic derangement. neurodegenerative disorders may present with parkinsonism, and are also referred to as atypical parkinsonism or parkinson plus syndromes (illnesses with parkinsonism plus some other symptoms distinguishing them from pd) including 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 with dementia known as parkinson's disease dementia. the relationship between pd and dlb is complex and incompletely understood. it represents a continuum with variable distinguishing clinical and pathological attributes, or it 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 cerebral stroke). the damaging of the dopaminergic pathways is similar in cause for both vascular parkinsonism and idiopathic pd, and so present with similar symptoms. differentiation can be made with careful bedside examination, history evaluation, and imaging. pathophysiology 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 disease the 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). 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. 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 an increase in the number of microglia (another type of glial cell) in the substantia nigra. severity of progression of the parts of the brain affected by pd can be measured with braak staging. 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. schematic initial progression of lewy body deposits in the first stages of pd, as proposed by braak and colleagueslocalization 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 five major pathways in the brain connect other brain areas to the basal ganglia. these are known as the motor, oculomotor, associative, limbic, and orbitofrontal circuits. names indicate the main projection area of each circuit. all are affected in pd, and their disruption causes movement-, attention- and learning-related symptoms of the disease. scientifically, the motor circuit has been examined the most intensively. an illustration of the dopamine pathways throughout the brain since 1980, a particular conceptual model of the motor circuit and its alteration with pd has been of influence although some limitations have been pointed out which have led to modifications. in this model, the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. when a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in pd, demand greater exertions of effort for any given movement. the end result 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 one mechanism causing brain cell death results from abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in damaged cells. this insoluble protein accumulates inside neurons forming inclusions, known as lewy bodies. these bodies first appear in the olfactory bulb, medulla oblongata and pontine tegmentum; individuals at this stage may be asymptomatic or 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. these brain sites are the main places of neuronal degeneration in pd, but lewy bodies may be protective from cell death (with the abnormal protein sequestered or walled off). other forms of alpha-synuclein (eg oligomers) that are not aggregated into lewy bodies and lewy neurites, may in fact 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 uncommon unless the person has dementia. other mechanisms include proteasomal and lysosomal systems dysfunction and reduced mitochondrial activity. iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. it may be related to oxidative stress, protein aggregation, and neuronal death, but the mechanisms are obscure. the neuroimmune connection the neuroimmune interaction is heavily implicated in pd pathology. pd and autoimmune disorders share genetic variations and molecular pathways. some autoimmune diseases may even increase one's risk of developing pd, up to 33% in one study. autoimmune diseases linked to protein expression profiles of monocytes and cd4+ t cells are linked to pd. herpes virus infections can trigger autoimmune reactions to alpha-synuclein, perhaps through molecular mimicry of viral proteins. alpha-synuclein, and its aggregate form, lewy bodies, can bind to microglia. microglia can proliferate and be over-activated by alpha-synuclein binding to mhc receptors on inflammasomes, bringing about a release of proinflammatory cytokines like il-1β, ifnγ, and tnfα. activated microglia influence the activation of astrocytes, converting their neuroprotective phenotype to a neurotoxic one. astrocytes in healthy brains serve to protect neuronal connections. in pd patients, astrocytes cannot protect the dopaminergic connections in the striatum. microglia present antigens via mhc-i and mhc-ii to t cells. cd4+ t cells, activated by this process, are able to cross the blood brain barrier (bbb) and release more proinflammatory cytokines, like interferon-γ (ifnγ), tnfα, and il-1β. mast cell degranulation and subsequent proinflammatory cytokine release is implicated in bbb breakdown in pd. another immune cell implicated in pd are peripheral monocytes and have been found in the substantia nigra of pd patients. these monocytes can lead to more dopaminergic connection breakdown. in addition, monocytes isolated from pd patients express higher levels of the pd-associated protein, lrrk2, compared with non-pd individuals via vasodilation. in addition, high levels of pro-inflammatory cytokines, such as il-6, can lead to the production of c-reactive protein by the liver, another protein commonly found in pd patients, that can lead to an increase in peripheral inflammation. peripheral inflammation can affect the gut-brain axis, an area of the body highly