Parkinson's disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D. Alberto Castro Molina, M.D.

Parkinson’s disease is a degenerative disorder of the central nervous system that often impairs the sufferer’s motor skills and speech. ^[1]

Parkinson’s disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.

Nonmotor features are common and may precede motor symptoms by years, including constipation, rapid eye movement sleep behavior disorder, depression, anxiety, and olfactory dysfunction. ^[1][2] Parkinson’s disease is defined clinically by the presence of parkinsonism, and pathologically is characterized by loss of dopaminergic neurons in the substantia nigra and accumulation of misfolded alpha-synuclein in Lewy bodies and Lewy neurites in most cases. ^[3][1]

PD is the most common cause of parkinsonism, a group of similar symptoms. PD is also called “primary parkinsonism” or “idiopathic PD” (having no known cause). While most forms of parkinsonism are idiopathic, there are some cases where the symptoms may result from toxicity, drugs, genetic mutation, head trauma, or other medical disorders. ^[1]

the first person who documented and recognized Parkinson’s disease was a British physician, James Parkinson in 1817 who named it paralysis agitans. The first underlying pathology of Parkinson disease was described by a German pathologist Frederick Lewy in 1912. He described that there are cytoplasmic inclusions in some brain areas of PD patients. in 1967 the drug “L-dopa” was introduced to the market as a treatment of Parkinson ’s disease.

The modern era of treatment includes levodopa-based symptomatic therapy and evidence-based use of device-aided therapies such as deep brain stimulation for selected patients with motor fluctuations and dyskinesias. ^[4][5]

The underlying pathophysiology of Parkinson disease is dopamine depletion. Reduced number of dopaminergic neurons lead to increased inhibition of thalamus and as a result, decrease excitation of brain cortex, causing bradykinesia. pathologic hallmark of PD is lewy bodies which are round cytoplasmic eosinophilic inclusions. This disease can have so many triggers ( Protein misfolding, Defective proteolysis, Mitochondrial dysfunction, Oxidative stress, Iron metabolism and Immunologic and inflammatory mechanisms) but the main etiology of neuronal degeneration is either apoptosis or necrosis.

Lewy bodies and Lewy neurites contain aggregated alpha-synuclein, and alpha-synuclein–related biology and neuroinflammation are implicated in disease mechanisms. ^[3][6][7]

although most of the cases of Parkinson disease are sporadic and idiopathic, there are some underlying cause for this disease including: Genetics, drugs, oxidative stress, iron metabolism, immunologic and inflammatory mechanisms and protein misfolding.

Both genetic susceptibility and environmental exposures contribute to Parkinson’s disease risk. ^[1][8] Twin studies support an important role for non-genetic factors, especially for typical late-onset Parkinson’s disease. ^[9] Associations have been reported for pesticide exposure and specific toxicants (including rotenone and paraquat). ^[10][11]

Differential diagnosis for Parkinson disease includes: Essential tremor, scans without evidence of dopaminergic deficit (SWEDD), dementia with Lewy bodies, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy and idiopathic, familial basal ganglia calcification and Secondary parkinsonism

Clinical diagnostic criteria for Parkinson’s disease emphasize bradykinesia plus rest tremor and/or rigidity, supportive features, and exclusion criteria and red flags for atypical parkinsonism. ^[12] Differentiation from atypical parkinsonism may be supported by disorder-specific clinical criteria for progressive supranuclear palsy and multiple system atrophy. ^[13][14]

The incidence of parkinson disease is 8 to 18.6 per 100,000 person-years. The prevalence of Parkinson disease is about 0.3% in 40 years old people and older. According to this prevalence currently we have 7.5 million people affected by this disease. The prevalence of PD can rise with age. In 40 to 49 years old people the prevalence is 41 per 100,000 and in 80 years old and older people its 1900 per 100,000 people. Some studies suggest that men have a higher risk of developing Parkinson disease than women. In the study of Stephen K. Van Den Eeden and colleges it was suggested that the incidence of PD from higher to lower is in Hispanic, non-Hispanic whites and blacks.

Population-based studies and Global Burden of Disease analyses show that Parkinson’s disease prevalence and incidence rise sharply with age and that the global burden is increasing. ^[15] Contemporary U.S. projections suggest continued growth in the number of affected individuals over coming decades. ^[16] Incidence estimates and variation by age, sex, and race/ethnicity have been described in U.S. cohorts. ^[17][18]

Common risk factors in the development of Parkinson disease are:

Family history, Depression, exposure to pesticides, high consumption of dairy diet, Vitamin D deficiency, history of brain trauma, history of migraine with aura, history of anemia, using of well water, excess intake of iron and manganese, Obesity, exposure to hydrocarbons solvents and low muscle strength.

Among modifiable exposures, pesticide exposure has been associated with increased risk in observational studies, though causality and the contribution of confounding vary by exposure and study design. ^[10][11] Genetic susceptibility influences both risk and heterogeneity in clinical presentation and progression. ^[8][1]

The most common initiating symptoms in PD are slowness of movement (bradykinesia), shaking hands while they are at rest (resting tremor) and muscle stiffness (rigidity).These symptoms usually starts unilaterally and the severity of them remains higher in the side of onset.

Complications that can develop as a result of Parkinson disease includes:

Tremor, rigidity, Bradykinesia, Gait problems, Cognitive dysfunction and dementia, Psychosis and hallucinations, mood disorders including depression, anxiety, and apathy/abulia, sleep disturbances, Fatigue, Olfactory dysfunctio, pain, Autonomic dysfunction including orthostatic hypotension, constipation, dysphagia, urinary and sexual problems. In one of the studies regarding PD prognosis, it was seen that the percent of dead or severely disabled patients is 25 percent within 5 years, 67 percent within 5 to 9 years and 80 percent within 10 to 14 years of disease onset. It was also shown that disability will occurs mostly in 3 to 7 years of disease onset.

Dementia is a common late complication of Parkinson’s disease, and clinical diagnostic criteria for Parkinson’s disease dementia have been established. ^[19] Parkinson’s disease psychosis and dementia-related psychosis can substantially affect quality of life and caregiver burden. ^[1]

Common symptoms of Parkinson disease includes: Tremor, rigidity, bradykinesia, Cognitive dysfunction and dementia, psychosis and hallucinations, mood disorders including depression, anxiety, and apathy/abulia, sleep disturbances, fatigue, olfactory dysfunction, pain and autonomic dysfunction.

In the appearance of PD patients we can notice that the blinking rate of spontaneous blinking is lower than normal but voluntary blinking is similar to general population. The other finding in PD patient is that their spontaneous facial expressions are less frequent and less varied in comparison to normal people (hypomimia) In physical examination the have Cogwheel rigidity, Resting tremor, Gait problems, Bradykinesia, Olfactory dysfunction and Orthostatic hypotension.

There are no diagnostic lab findings associated with Parkinson’s disease

On brain CT scan, Parkinson disease is characterized by cortical and subcortical atrophy.

Neuroimaging in typical Parkinson’s disease is often normal or nonspecific early in the course; CT and MRI are commonly used to evaluate for alternative diagnoses and atypical parkinsonism. ^[1]

MRI findings in Parkinson disease are: reduction in T2 relaxation time and reduced iron content in putamen and GPe.

We can also use MRI to differentiate PD from other conditions. for example in the midbrain, thinning of anteroposterior diameter and enlargement of third ventricle in suggestive of supranuclear palsy. Also we can see atrophy of brainstem and cerebellum in multiple system atrophy.

PET scan: In PET scan we can see that the uptake of [18F]-flurodopa tracer in reduce in the caudate and putamen in PD patients.

DaTscan: This technique can help us differentiate healthy individuals or patients with essential tremor from diseases with nigrostriatal degeneration (PD, MSA, PSP, and cortical degeneration). ^[20]

Sonography: In sonography of PD patient’s brain we can see hyperechogenicity of the STN.

Response to dopaminergic therapy: One of the useful methods in diagnosing PD is patient response to dopaminergic therapy. Levodopa and apomorphine challenge tests in proven to be useful in distinguishing PD from other parkinsonian syndromes.

Autonomic testing: Autonomic testing including cardiac sympathetic denervation, urodynamic testing, anal or urethral EMG, sympathetic skin responses, quantitative sudomotor axon reflex test, tilt table test and heart rate variability during forced respirations are also useful in diagnosing PD.

Olfactory testing: Olfactory testing is a useful test since olfactory dysfunction in common in PD but not in other parkinsonian syndromes and essential tremor.

Clinical diagnostic criteria for Parkinson’s disease emphasize bradykinesia plus rest tremor and/or rigidity, supportive features, and exclusion criteria/red flags. ^[12]

Biomarker development is an active area of research. Detection of phosphorylated alpha-synuclein in skin biopsy specimens has shown diagnostic utility for synucleinopathies in recent studies, though its role in routine care and staging continues to evolve. ^[21]

The mainstay of therapy for motor symptoms of Parkinson disease are: Levodopa, dopamine agonists, monoamine oxidase (MAO) B inhibitors, anticholinergic agents, amantadine, catechol-O-methyl transferase (COMT) inhibitors, estrogen and other drugs such as Exenatide, uric acid, isradipine, nilotinib and GDNF infusion.

Evidence-based reviews and guidelines summarize pharmacologic options for motor symptoms and motor complications, including levodopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors, amantadine, and adenosine A2A antagonists, with individualized selection based on age, symptom burden, cognitive status, and risk of adverse effects. ^[22][1]

Treatment choices for some of the nonmotor symptoms of PD are:

psychosis: quetiapine, clozapine and pimavanserin. Pimavanserin has demonstrated efficacy in dementia-related psychosis. ^[23]

Dementia: Cholinesterase inhibitors such as rivastigmine and donepezil. ^[19]

Fatigue: Amantadine, methylphenidate and pemoline.

Depression: Amitriptyline, desipramine, citalopram ,paroxetine, venlafaxine, ropinirole and pramipexole.

Constipation: Increasing probiotics and fibers, lubiprostone and polyethylene glycol.

Sialorrhea: chewing gum and hard candy but in severe cases, botulinum toxin injection into salivary glands .

Sexual dysfunction: sildenafil (for male)

Ortostatic hypotention: Fludrocortisone, Sympathomimetic agents such as ephedrine, pseudoephedrine, methylphenidate and dextroamphetamine.

Disease-modifying therapies remain an unmet need. Several alpha-synuclein–targeted immunotherapy trials have not shown clinical benefit in early Parkinson’s disease. ^[24][25] A randomized trial of the GLP-1 receptor agonist lixisenatide reported effects on motor outcomes in early Parkinson’s disease, and further studies are ongoing to clarify clinical meaningfulness and durability. ^[26]

The delayed-start rasagiline trial has been discussed in the context of disease modification, though interpretation remains complex. ^[27]

Deep brain stimulation: Deep brain stimulation in the most common surgical treatment of Parkinson disease and is shown to be effective in improving motor function in these patient especially when it’s done bilaterally. ^[4][5]

Thalamotomy and pallidotomy: Unilateral pallidotomy can reduce dyskinesia, on and off fluctuations, tremor, rigidity, bradykinesia and gait problems but it is not as effective as DBS.

Subthalamotomy: unilateral subthalamotomy is useful in managing PD symptoms.

Contemporary guidance reviews invasive therapies for Parkinson’s disease, including DBS and lesioning procedures such as focused ultrasound and radiofrequency ablation in selected patients. ^[28]

Effective measures for the primary prevention of multiple sclerosis include staying away from modifiable risk factors of the Parkinson disease:

Depression, exposure to pesticides, high consumption of dairy diet, Vitamin D deficiency, history of brain trauma, history of anemia, using of well water, excess intake of iron and manganese, Obesity, exposure to hydrocarbons solvents and low muscle strength.

There are currently no proven measures for primary prevention of Parkinson’s disease; associations with modifiable exposures have been reported, but causal inference and preventive interventions remain areas of ongoing research. ^[1][10][11]

There is no established method for secondary prevention of Parkinson disease.

Digital health tools are being studied to quantify early disease features and progression in observational cohorts. ^[29]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Parkinson disease was first documented and recognized by a British physician, James Parkinson in 1817 who named it paralysis agitans. The first underlying pathology of Parkinson disease was described by a German pathologist Frederick Lewy in 1912. He described that there are cytoplasmic inclusions in some brain areas of PD patients. in 1967 the drug “L-dopa” was introduced to the market as a treatment of Parkinson ’s disease.

• Parkinson disease was first documented and recognized by a British physician, James Parkinson in 1817 who named it paralysis agitans.^[1]
• The current name of the disease (Parkinson disease) is from Jean-Martin Charcot.^[2]
• The first underlying pathology of Parkinson disease was described by a German pathologist Frederick Lewy in 1912. He described that there are cytoplasmic inclusions in some brain areas of PD patients.^[1]
• Later on in 1919 Tretiakoff showed that in this patients’ substantia nigra there are evidences of neuronal loss.
• Finally in the 1950s dopamine depletion was known to be the underlying cause of the disease.^[3]
• Later, in 1967 the drug “L-dopa” was introduced to the market as a treatment of Parkinson ’s disease.^[4][5][6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

The underlying pathophysiology of Parkinson disease is dopamine depletion. Reduced number of dopaminergic neurons lead to increased inhibition of thalamus and as a result, decrease excitation of brain cortex, causing bradykinesia. pathologic hallmark of PD is lewy bodies which are round cytoplasmic eosinophilic inclusions. This disease can have so many triggers ( Protein misfolding, Defective proteolysis, Mitochondrial dysfunction, Oxidative stress, Iron metabolism and Immunologic and inflammatory mechanisms) but the main etiology of neuronal degeneration is either apoptosis or necrosis.

• The substantia nigra (SN), striatum (caudate and putamen), globus pallidus (GP), subthalamic nucleus (STN) and thalamus contribute with each other to make the extrapyramidal system or basal ganglia.
• The impulses from hippocampus, amygdala and prefrontal supplementary motor area to the basal ganglia are excitatory mediated by glutamate.
• The major dopaminergic neurons are in substantia nigra and are responsible for dopaminergic input of striatum. The striatal output is inhibitory (GABA) despite the excitatory (glutamate) output of STN to the globus pallidus (medial and lateral).
• There are 5 dopamine receptors (D1_D5) which are in basal ganglia and limbic system. D1 and D2 are mostly found in the dorsal striatum (motor) and are activated through dopaminergic pathway from SNc, as a result, they are very important in the pathophysiology of Parkinson disease. D3 and D4 are located mostly in mesolimbic or emotional part of the brain and D5 in hippocampus/hypothalamus area.^[1]

• The underlying pathophysiology of Parkinson disease is dopamine depletion. In the course of the disease dopamine depletion of nigrostriatal pathway will lead to denervation hypersensitivity and increasing number of D2 receptors in dorsal putamen.^[2]
• There are two pathways in this system: Direct and indirect pathway.
• Indirect pathway starts with inhibition of striatum via D2 receptor which in turn inhibits neurons of lateral GP by GABA which inhibits the inhibition of STN by lateral GP. STN provides excitatory action on GP internal and SNr via glutamate. GPi inhibit thalamus by GABA but cortex input from thalamus is excitatory.
• Direct pathway starts with excitation of striatum by stimulation of D1 receptors, then striatum inhibits GP internal and SNr by GABA directly. Reduced number of dopaminergic neurons lead to increased inhibition of thalamus and as a result, decrease excitation of brain cortex, causing bradykinesia.^[3]
• Our brain has some compensatory mechanism fighting dopamine depletion. It can increase the synthesis of dopamine, gap junctions and the number of D2 receptors.^[4][5] It can also reduce the uptake of dopamine from synaptic space.^[6]
• The main pathology seen in PD patients is neuronal loss, depigmentation and gliosis which are mostly seen in the locus ceruleus and substantia nigra. The normal number of pigmented neurons in SN in a normal individual is about 550,000, but in patient with PD in can decrease as much as 66%.^[7]
• In the normal aging process, neuronal loss occurs in the dorsal tier of SN pars compacta and the most of dopamine depletion is seen in caudate nucleus. But in Parkinson, loss of dopaminergic neurons occurs predominantly in ventrolateral portion of the SN.^[8][9]
• The other sites of the brain which are influenced by PD are internal segment of the globus pallidus, center median parafascicular complex, pedunculopontine tegmental nucleus, glutamatergic caudal intralaminar thalamic nuclei and hippocampus.^[10][11]
• PD may have so many triggers but the main etiology of neuronal degeneration is either apoptosis or necrosis.^[12][13][14]

• One of the main underlying cause of PD is mutation in the gene of alpha-synuclein protein which is abundant in the CNS.
• Its function is thought to be involved in synaptic function and plasticity.^[15][16]
• This mutations lead to unfold alpha-synuclein and aggregation of insoluble protein and neuronal damage.
• Lewy bodies which are characteristic of PD are mostly build from alpha-synuclein protein.^[17]

• There are three pathways which control the protein homeostasis in cells: Molecular chaperons, the ubiquitin-proteasome system and autophagy-lysosomal pathway.
• Alpha synuclein processing is done by all of this three mechanisms and defect in any of them can cause aggregation of this protein and neuronal death.^[18][19][20]

• The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an analog of mepridine is found to be associated with PD.
• The oxidation of this drug produces 1-methyl-4-phenylpyridium which inhibits complex one of mitochondria and result in cell damage.
• Studies showed that the activity of this complex is decreased in PD patients.^[21][22][23]

• Reactive oxygen species including hydrogen peroxide, superoxide anions and hydroxyradicals are toxic to neurons and cause neuronal damage.
• They interact with membrane lipids and cause lipid peroxidation which can be seen in substantia nigra of PD patients.^[24][25]
• They can also cause protein misfolding by attacking disulfide isomerase through nitric oxide. Disulfide isomerase is a chaperone preventing the aggregation of proteins.^[26]

• Studies showed that impaired iron metabolism leads to increase amount of iron in substantia nigra of PD patients.
• One of the underlying etiology of iron accommodation in neuronal cells is the absence of tau protein.^[27][28][29]

• There are some studies supporting the idea of immunologic mechanisms causing PD.^[30]
• In PD patients there is elevated amounts of cyclooxygenase-2 which is the rate limiting enzyme in prostaglandin E2 synthesis.^[31]
• Neuronal cell death can also occur due to infiltration of CD4+ T cells.^[32]

• There are some evidence showing that there is an association between PD and genetic.
• This role is higher when Parkinson disease occurs in the individual younger than 50 years old.^[33]
• These studies also demonstrate that if a person has a first degree with PD, the risk of developing PD is 2 to 3 times higher than normal population. Conversely, in 25 to 50 % of PD patients we can find at least one first degree having PD.^[34]

Some of specific genes involving in PD are:

• Glucocerebrosidase gene ^[35]
• SNCA-associated PD ^[36]
• LRRK2-associated PD ^[37]
• Parkin-associated PD ^[38]
• PINK1-associated PD ^[39]
• DJ-1-associated PD ^[40]

• The pathologic hallmark of PD is the presence of lewy bodies, which are round cytoplasmic eosinophilic inclusions. The content of these bodies are mostly alpha synuclein and ubiquitin, but we can also find complement proteins, microflament subunits, and parkin substrate protein.^[41]

• The pathologic manifestations of apoptosis include condensation of chromatin and cytoplasm, fragmentation of cell and lysosome-mediated phagocytosis.^[42] Neuronal apoptosis occurs in normal individuals (0.5 percent of substantia nigra neurons) but in PD patients this can be as high as 2 percent.^[43][44].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Parkinson disease must be differentiated from other diseases that can mimic this disease clinically or radiologically such as: essential tremor, scans without evidence of dopaminergic deficit (SWEDD), dementia with Lewy bodies, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, idiopathic and familial basal ganglia calcification, and secondary parkinsonism.

• Parkinson disease must be differentiated from other diseases that can mimic this disease clinically or radiologically such as:

• Essential tremor is demonstrated by bilateral resting tremor of arms, head, chin and trunk. Tremor of PD is action tremor and it seems to be easy to differentiate it from resting tremor of ET but sometimes we can see resting tremor in PD patient and conversely action tremor in ET patients.^[1][2]

• Patients with scans without evidence of dopaminergic deficit have upper extremity resting tremor but their disease does not progress to the complete PD and there are no evidence of dopamine depletion in their NS.^[3]

• Dementia will finally occurs in the most cases of Parkinson disease but the timing of dementia in PD is after full developing of PD and mostly after at least one year of disease start date. When dementia occurs with or before the signs and symptoms of Parkinson disease we will categorize it as dementia with lewy body.^[4][5]

• MSA is an idiopathic disease^[6] characterized by autonomic problems such as urogenital dysfunction, ataxia and parkinsonism symptoms.^[7] MSA patients have resting tremor in arms, rigidity and bradykinesia.^[8] The underlying pathophysiology of MSA is myelin dysfunction and inclusions in glial cell throughout CNS.^[6][9]

• Clinical features of CBD is asymmetric movement disorders including rigidity, akinesia and dystonia.^[10][11][12] cognitive disorder is very common in this disease and can be the presenting sign of it.^[13][14] there are evidences of asymmetric frontoparietal cortical atrophy in autopsy in CBD patients. In microscopic evaluation there are neuronal loss, ballooned achromatic and gliosis.^[15][16]

• Abnormal gait is the most common presentation of PSP disease. As opposed to idiopathic Parkinson disease, their trunk is extended and arms are abducted. They commonly fall from behind leading to bruises and lacerations.^[17] They can also have supranuclear ophthalmoparesis or ophtalmoplegia.^[18]

• Accumulation of calcium in some brain regions and the basal ganglia is known as idiopathic basal ganglia calcification or bilateral striatopallidodentate calcinosis. Some of these patients can have parkinsonism symptoms such as dystonia, ataxia and chorea mostly between ages 20_60.^[19][20]
• The autosomal dominant form of the disease which is known as familial form can be the result of several mutations such as:^[21]
  • The SLC20A2 gene on chromosome 8p11.2 ^[22]
  • The PDGFRB gene on chromosome 5q32 ^[23]
  • The PDGFB gene on chromosome 22q13.1 ^[24][25]
  • The XPR1 gene on chromosome 1q25.3 ^[26]

• Vascular parkinsonism:^[27]
  • Some studies suggest that in old ages, microscopic and lacunar infarction or atherosclerosis in basal ganglia can cause Parkinsonism symptoms.

• Drug-induced parkinsonism: ^{[28][29][30][31][32]}
  • The most common type of secondary parkinsonism is drug induced PD.
    • Antiemetic and antipsychotic drugs are mostly the cause.
  • They can cause akathisia and orofacial dyskinesia which in these cases we can differentiate them from idiopathic PD but sometimes they are similar to PD and have symmetrical resting tremor.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

The incidence of parkinson disease is 8 to 18.6 per 100,000 person-years. The prevalence of Parkinson disease is about 0.3% in 40 years old people and older. According to this prevalence currently we have 7.5 million people affected by this disease. The prevalence of PD can rise with age. In 40 to 49 years old people the prevalence is 41 per 100,000 and in 80 years old and older people its 1900 per 100,000 people. Some studies suggest that men have a higher risk of developing Parkinson disease than women. In the study of Stephen K. Van Den Eeden and colleges it was suggested that the incidence of PD from higher to lower is in Hispanic, non-Hispanic whites and blacks.

• The incidence of parkinson disease is 8 to 18.6 per 100,000 person-years.^[1]

• The prevalence of Parkinson disease is about 0.3% in 40 years old people and older. According to this prevalence currently we have 7.5 million people affected by this disease.^[2][3]

• The prevalence of PD can rise with age. In 40 to 49 years old people the prevalence is 41 per 100,000 and in 80 years old and older people its 1900 per 100,000 people.^[2]

• Some studies suggest that men have a higher risk of developing Parkinson disease than women.^[1][2][4]

• In the study of Stephen K. Van Den Eeden and colleges it was suggested that the incidence of PD from higher to lower is in Hispanic, non-Hispanic whites and blacks.^[5]

• The majority of [disease name] cases are reported in [geographical region].

• [Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Common risk factors in the development of Parkinson disease include family history, depression, exposure to pesticides, high consumption of dairy diet, Vitamin D deficiency, history of brain trauma, history of migraine with aura, history of anemia, using of well water, excess intake of iron and manganese, Obesity, exposure to hydrocarbons solvents and low muscle strength.

Common risk factors in the development of Parkinson disease are:

• Family history^[1]
• Depression^[2]
• Exposure to pesticides^[1]
• high consumption of dairy diet^[3]
• Vitamin D deficiency^[4]
• History of brain trauma^[5]

• History of migraine with aura^[6]
• History of anemia^[7]
• Using of well water^[8]
• Excess intake of iron and manganese^[9]
• Obesity^[10]
• Exposure to hydrocarbons solvents^[11]
• Low muscle strength^[12]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

The most common initiating symptoms in PD are slowness of movement (bradykinesia), shaking hands while they are at rest (resting tremor) and muscle stiffness (rigidity). These symptoms usually starts unilaterally and the severity of them remains higher in the side of onset. Complications that can develop as a result of Parkinson disease include tremor, rigidity, bradykinesia, gait problems, cognitive dysfunction and dementia, psychosis and hallucinations, mood disorders including depression, anxiety, and apathy/abulia, sleep disturbances, fatigue, olfactory dysfunction, pain, autonomic dysfunction including orthostatic hypotension, constipation, dysphagia, urinary and sexual problems. In one of the studies regarding PD prognosis, it was seen that the percent of dead or severely disabled patients is 25 percent within 5 years, 67 percent within 5 to 9 years and 80 percent within 10 to 14 years of disease onset. It was also shown that disability will occurs mostly in 3 to 7 years of disease onset.

• The most common initiating symptoms in PD are slowness of movement (bradykinesia), shaking hands while they are at rest (resting tremor) and muscle stiffness (rigidity).^[1]
• These symptoms usually starts unilaterally and the severity of them remains higher in the side of onset.^[2]

• In the course of the disease patients may experience motor and nonmotor symptoms:

• Tremor: Tremor is the most common symptom in Parkinson disease and can be the presenting sign in 70 to 80 percent of patients.^[3][1]
• This symptom starts unilaterally mostly in hand and then progress to the other side of the body. It can also involve legs, jaw, lips and tongue.^[4][5][6]
• PD tremor frequency is 3 to 7 Hz.^[4]
• There is a symptom called re-emergent tremor in some of the PD patients. It manifests by postural tremor that starts after several seconds and can make it difficult to differentiate PD from essential tremor.^[7][8]

• Rigidity: Rigidity in PD in very common and can be seen in 75 to 90 percent of patients.^[3][1][9]
• It commonly starts in the same side as the tremor. PD patients have increased resistance to passive movement of their joint and sometimes it’s known as cogwheel rigidity because of the ratchety pattern of resistance and relaxation. Some evidences suggest that superimposition of tremor on increased muscle tone creates this kind of rigidity.^[10][11]

• Bradykinesia: Bradykinesia or slowness of movement, is seen in 80 percent of PD patients.^[1]
• Postural instability: Gait and postural problems can be the main cause of disability in PD patients and commonly doesn’t response well to dopaminergic treatment.^[12][13]

• Cognitive dysfunction and dementia: Cognitive impairment can occur in the PD but in some ways it’s different from Alzheimer disease. Language dysfunction and memory deficit is less prominent while executive and visuospatial dysfunction is more prominent in PD.^{[14][15][16][17][18]}
• Parkinson’s diseases memory deficits are in the area of retrieval of learned information. Aphasia, apraxia and sever memory loss are uncommon in PD.^{[19][20][21][22]}

• Psychosis and hallucinations: Psychosis, especially visual hallucination occurs in PD patients who are under treatment.^[23][24][25]
• All of the antiparkinsonism drugs can cause this but dopamine agonists are the most common cause.^[26]
• Severity and prevalence of these hallucinations increase over time but can resolve when PD medications are discontinued.^[27][28]

• Mood disorders including depression, anxiety, and apathy/abulia:
  • Depression: Mild to moderate depression is very common in PD and can be seen in 50 percent of PD patients.^[29][30][31] these patients can present with anhedonia, sadness, guilt and feeling of worthlessness.^[32]
  • Anxiety: Anxiety, especially generalized anxiety disorder and social phobia is common in PD and can be seen in more than 30 percent of patients.^[29][33] Anxiety is usually combined by depression.^[34]
  • Apathy and abulia: Apathy and abulia are characterized by lack of motivation, speech, emotional and motor function. The pathophysiology behind this symptom is involvement of frontal lobe in PD patients.^[35][36]

• Sleep disturbances: Sleep disorders is seen in 55 to 80 percent of PD patients in early or late stages of the disease.^[37][38] approximately 40 percent of PD patients take medicine for sleep cause insomnia is as common as 60 percent in them.^[37][38][39]
• The most common cause of insomnia and frequent awakening during sleep include nocturia, cramp, pain, nightmares and tremor.^{[39][40][41][42][43]}
• Another sleep disorder which can be seen in these patients is REM sleep behavior disorder (RBD), characterized by vigorous movement because of increased muscle tone.^[44][45]
• Fatigue: The prevalence of fatigue in PD patients is 33 to 58 percent^[46][47][48]
• It’s mostly associated with depression and excessive day time somnolence but can occur as an isolate problem too.^[48][47][49]
• Olfactory dysfunction: Deficits in odor identification and discrimination are common in PD and can happen even before the motor symptoms of the disease.^[50][51][52]
• Pain: 46 percent of PD patients experience pain as a sense of lancinating, burning or tingling. The pain can be generalized or localized and can happen in different body areas like face, joints and genitals.^[53][54][55]

• Autonomic dysfunction: Autonomic dysfunction includes orthostatic hypotension, constipation, dysphagia, urinary and sexual problems.^[56][57]
• Urinary symptoms is mostly cause by reduced bladder capacity due to detresor muscle contraction and manifest as frequency, urgency and urge incontinence.^[58][59]
• Sexual dysfunction in men manifest with erection dysfunction and in women with vaginal tightness and lack of orgasm.^[60][61]

• Complications that can develop as a result of Parkinson disease, may be equal to disease symptoms such as:
  • Tremor^[3][1]
  • Rigidity^[3][1][9]
  • Bradykinesia^[1]
  • Gait problems^[12][13]
  • Cognitive dysfunction and dementia^{[14][15][16][17][18]}
  • Psychosis and hallucinations^[23][24][25]
  • Mood disorders including depression, anxiety, and apathy/abulia^{[29][30][31][33][35][36]}
  • Sleep disturbances^[37][38]
  • Fatigue^[46][47][48]
  • Olfactory dysfunction^[50]
  • Pain^[53][54][55]
  • Autonomic dysfunction including orthostatic hypotension
  • constipation
  • dysphagia
  • urinary and sexual problems.^[56][57].

• In one of the studies regarding PD prognosis, it was seen that the percent of dead or severely disabled patients is 25 percent within 5 years, 67 percent within 5 to 9 years and 80 percent within 10 to 14 years of disease onset.^[62][63] It was also shown that disability will occurs mostly in 3 to 7 years of disease onset.^[64]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Cognitive impairment and dementia can occur in the PD but in some ways it’s different from Alzheimer disease. Language dysfunction and memory deficit is less prominent while executive and visuospatial dysfunction is more prominent in PD. Parkinson’s diseases memory deficits are in the area of retrieval of learned information. Aphasia, apraxia and sever memory loss are uncommon in PD.

Cognitive impairment and dementia can occur in the PD but in some ways it’s different from Alzheimer disease. Language dysfunction and memory deficit is less prominent while executive and visuospatial dysfunction is more prominent in PD.^{[1][2][3][4][5]} Parkinson’s diseases memory deficits are in the area of retrieval of learned information. Aphasia, apraxia and sever memory loss are uncommon in PD.^[6][7][8][9]

The prevalence of major or mild neurocognitive disorder due to parkinson’s disease is:

75,000 per 100,000 (75%) major neurocognitive disorder.

27,000 per 100,000 (27%) mild neurocognitive disorder.^[10]

Risk factors for developing Cognitive impairment and dementia in Parkinson disease are: Duration of PD, severity of the disease, age of onset >60 years, old age, presence of rapid eye movement sleep behavior disorder, autonomic dysfunction, gait problem and hyposmia.^{[11][12][13][14][15][16][6][7][17]}

the differential diagnosis for PDD includes:

• Alzheimer disease^[18][19]
• Dementia with Lewy bodies^[20][21]
• Multiple system atrophy^[22][23]
• Corticobasal degeneration^[24]
• Progressive supranuclear palsy^[25][26][27]
• vascular parkinsonism^[28]