Parkinson's disease overview
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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.
Overview
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]
Historical Perspective
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]
Pathophysiology
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]
Causes
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]
Differentiating Parkinson disease from Other Diseases
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]
Epidemiology and Demographics
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]
Risk Factors
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]
Natural History, Complications, and Prognosis
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]
Diagnosis
History and Symptoms
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.
Physical Examination
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.
Laboratory Findings
There are no diagnostic lab findings associated with Parkinson's disease
CT scan
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
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.
Other Imaging Findings
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.
Other Diagnostic Studies
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]
Treatment
Medical Therapy
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]
Surgery
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]
Primary Prevention
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]
Secondary Prevention
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]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 Tanner CM, Ostrem JL (2024). "Parkinson's Disease". N Engl J Med. 391 (5): 442–452. doi:10.1056/NEJMra2401857.
- ↑ Heinzel S, Berg D, Gasser T; et al. (2019). "Update of the MDS research criteria for prodromal Parkinson's disease". Mov Disord. 34: 1464–1470.
- ↑ 3.0 3.1 Dickson DW, Braak H, Duda JE; et al. (2009). "Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria". Lancet Neurol. 8: 1150–1157.
- ↑ 4.0 4.1 Okun MS (2012). "Deep-brain stimulation for Parkinson's disease". N Engl J Med. 367: 1529–1538.
- ↑ 5.0 5.1 Schuepbach WMM, Rau J, Knudsen K; et al. (2013). "Neurostimulation for Parkinson's disease with early motor complications". N Engl J Med. 368: 610–622.
- ↑ Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V (2022). "Inflammation and immune dysfunction in Parkinson disease". Nat Rev Immunol. 22: 657–673.
- ↑ Panicker N, Ge P, Dawson VL, Dawson TM (2021). "The cell biology of Parkinson's disease". J Cell Biol. 220 (4): e202012095.
- ↑ 8.0 8.1 Blauwendraat C, Nalls MA, Singleton AB (2020). "The genetic architecture of Parkinson's disease". Lancet Neurol. 19: 170–178.
- ↑ Goldman SM, Marek K, Ottman R; et al. (2019). "Concordance for Parkinson's disease in twins: a 20-year update". Ann Neurol. 85: 600–605.
- ↑ 10.0 10.1 10.2 Wang A, Costello S, Cockburn M, Zhang X, Bronstein J, Ritz B (2011). "Parkinson's disease risk from ambient exposure to pesticides". Eur J Epidemiol. 26: 547–555.
- ↑ 11.0 11.1 11.2 Tanner CM, Kamel F, Ross GW; et al. (2011). "Rotenone, paraquat, and Parkinson's disease". Environ Health Perspect. 119: 866–872.
- ↑ 12.0 12.1 Postuma RB, Berg D, Stern M; et al. (2015). "MDS clinical diagnostic criteria for Parkinson's disease". Mov Disord. 30: 1591–1601.
- ↑ Höglinger GU, Respondek G, Stamelou M; et al. (2017). "Clinical diagnosis of progressive supranuclear palsy: the Movement Disorder Society criteria". Mov Disord. 32: 853–864.
- ↑ Wenning GK, Stankovic I, Vignatelli L; et al. (2022). "The Movement Disorder Society criteria for the diagnosis of multiple system atrophy". Mov Disord. 37: 1131–1148.
- ↑ GBD 2016 Parkinson’s Disease Collaborators (2018). "Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016". Lancet Neurol. 17: 939–953.
- ↑ Yang W, Hamilton JL, Kopil C; et al. (2020). "Current and projected future burden of Parkinson's disease in the U.S.". NPJ Parkinsons Dis. 6: 15.
- ↑ Van Den Eeden SK, Tanner CM, Bernstein AL; et al. (2003). "Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity". Am J Epidemiol. 157: 1015–1022.
- ↑ Willis AW, Roberts E, Beck JC; et al. (2022). "Incidence of Parkinson disease in North America". NPJ Parkinsons Dis. 8: 170.
- ↑ 19.0 19.1 Emre M, Aarsland D, Brown R; et al. (2007). "Clinical diagnostic criteria for dementia associated with Parkinson's disease". Mov Disord. 22: 1689–1707.
- ↑ Bega D, Kuo PH, Chalkidou A; et al. (2021). "Clinical utility of DaTscan imaging in the evaluation of patients with suspected Parkinsonian syndrome: a systematic review and meta-analysis". NPJ Parkinsons Dis. 7: 43.
- ↑ Gibbons CH, Levine T, Adler C; et al. (2024). "Skin biopsy detection of phosphorylated alpha-synuclein in patients with synucleinopathies". JAMA. 331: 1298–1306.
- ↑ Fox SH, Katzenschlager R, Lim SY; et al. (2018). "International Parkinson and Movement Disorder Society evidence-based review of treatments for the motor symptoms of Parkinson's disease". Mov Disord. 33: 1248–1266.
- ↑ Tariot PN, Cummings JL, Soto-Martin ME; et al. (2021). "Trial of pimavanserin in dementia-related psychosis". N Engl J Med. 385: 309–319.
- ↑ Lang AE, Siderowf AD, Macklin EA; et al. (2022). "Trial of cinpanemab in early Parkinson's disease". N Engl J Med. 387: 408–420.
- ↑ Pagano G, Taylor KI, Anzures-Cabrera J; et al. (2022). "Trial of prasinezumab in early-stage Parkinson's disease". N Engl J Med. 387: 421–432.
- ↑ Meissner WG, Remy P, Giordana C; et al. (2024). "Trial of lixisenatide in early Parkinson's disease". N Engl J Med. 390: 1176–1185.
- ↑ Olanow CW, Rascol O, Hauser R; et al. (2009). "A double-blind, delayed-start trial of rasagiline in Parkinson's disease". N Engl J Med. 361: 1268–1278.
- ↑ Deuschl G, Antonini A, Costa J; et al. (2022). "European Academy of Neurology and the Movement Disorder Society European Section guideline on invasive therapies for Parkinson's disease". Mov Disord. 37: 1360–1374.
- ↑ Adams JL, Kangarloo T, Tracey B; et al. (2023). "Using a smartwatch and smartphone to assess early Parkinson's disease in the WATCH-PD study". NPJ Parkinsons Dis. 9: 64.