Parkinson's disease (PD)
Overview
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by tremor, bradykinesia, rigidity, gait disorders, and a disturbance of posture, which was first described as a specific syndrome by James Parkinson in 1817 in “An Essay on the Shaking Palsy”.1, 2 PD imposes a serious burden on patients, healthcare providers and health authorities globally. PD continues to have manifold unmet needs in terms of understanding pathophysiology, early detection, reliable biochemical and/or biomarkers, diagnosis, and effective treatments. Earlier diagnosis and ongoing development of new drugs to slow or alter disease progression have the potential to improve the outlook for PD patients at present or in the near future.3
Epidemiology3,4,5,6
In industrialized countries, it was estimated to be 0.3% in the general population, 1.0% in people older than over 60 years old, and perhaps 3% of the population over 80 years of age affected by PD. PD prevalence is increasing with an estimated 2.1 million people with PD worldwide in 1990 rising to 6.1 million had PD globally in 2016.3, 4, 5 Incidence rates of PD are estimated to range between 8 and 18 per 100,000 person-years.5 Based on health care utilization estimations, PD incidence ranges from 5/100,000 to over 35/100,000 new cases yearly. Incidence increases 5 to 10 folds from the sixth to the ninth decades of life.6 PD prevalence also increases with age, as the global population aging, PD is expected to increase dramatically, doubling in the next two decades. Therefore, the societal and economic burden of PD will escalate, unless more effective treatments, cures or means of prevention are identified.6
Incidence and prevalence in Taiwan7
According to the analyzed data acquired from the Taiwan National Health Insurance Research Database (NHIRD) entries between 2002 and 2009, PD incidence and prevalence showed a significantly increasing trend, with a greater magnitude noted for prevalence than for incidence (87.3% versus 9.2%).7 The PD incidence and prevalence increased with age and were slightly higher in men than in women. The people with lower monthly incomes were at significantly increased adjusted incidence rate ratio (1.50 - 1.56) and adjusted prevalence rate ratio (1.66 - 1.71) of PD. Moreover, significantly higher PD incidence and prevalence were noted in areas with lesser urbanization.7
Facts about PD1,8,9
- PD is the second most common neurodegenerative disorder with only Alzheimer’s disease being more prevalent.1
- According to Taiwan NHIRD, more than 40,000 Taiwanese suffered from PD based on as of 2011.8
- The estimated prevalence of PD in Taiwan was 0.15-0.3% of general population, slightly lower than western countries.9
Pathophysiology1,2,3,5
The etiology of PD remains unclear but is considered to be multifactorial and heterogeneous.3 The pathological hallmark of PD is depigmentation of the substantia nigra (SN) and locus coeruleus with neuronal loss in the pars compacta of the SN.1 Both apoptosis and autophagy are involved in the process.1 PD is characterized by the loss of dopaminergic neurons in the pars compacta of the SN and by accumulation of misfolded a-synuclein, which is found in intra-cytoplasmic inclusions called Lewy bodies (LBs).5 In, brief, PD is characterized pathologically by degeneration of dopaminergic neurons in the substantia nigra of the midbrain, leading to pathophysiologic changes in the circuitry of the downstream basal ganglia.2
- Dopamine loss in the striatum11
Dopamine is a neurotransmitter that transmits chemical messages from one nerve cell to another across the synapse, a space between the presynaptic cell and the postsynaptic receptor. Prominent degeneration of dopaminergic neurons in the midbrain, and the consequent deficiency of dopamine in brain areas that receive dopaminergic inputs from those neurons, specifically the post-commissural putamen and other basal ganglia regions.11
- Lewy bodies5
Lewy bodies are intraneuronal, round, eosinophilic inclusions with a hyaline core and a pale peripheral halo that are composed of more than 90 proteins.5 The main components of LBs are α-synuclein and ubiquitin.5 α-synuclein has the propensity to misfold, become insoluble and form β-sheet-rich amyloid aggregates that accumulate and form intracellular inclusions.5 The intermediates in this aggregation process are the toxic that impair mitochondrial, lysosomal and proteasomal function, damage biological membranes and the cytoskeleton, alter synaptic function and cause neuronal degeneration.5 It has been estimated that at the time of the diagnosis up to 60% of dopaminergic neurons have been lost.5
Clinical Presentation1,10
PD is manifested by motor and nonmotor symptoms.1 The classic finding of PD are motor symptoms, and patients may not proactively volunteer nonmotor symptoms because they are unaware that the symptoms could be PD related.10
| Motor and non-motor symptoms of PD5 | |
|---|---|
| Motor symptoms | Non-motor symptoms |
| Tremor | Hyposmia |
| Rigidity | Psychiatric symptoms: depression, anxiety, apathy hallucinations, psychosis |
| Bradykinesia/akinesia/hypokinesia | Dementia/cognitive impairment |
| Postural instability | Sensory symptoms |
| Postural abnormalities (camptocormia, Pisa syndrome) | Genitourinary symptoms: urinary frequency, urgency, reduced libido, sexual dysfunction |
| Gait disturbances (freezing of gait, festination, start/target/obstacle hesitation) | Gastrointestinal symptoms: constipation, delayed/reduced stomach emptying |
| Alterations in blinking/eye movements | Dysphagia, sialorrhoea, dysarthria, hypophonia |
| Hypomimia | Disturbances of sleep and wakefulness |
| Micrographia | Cardiovascular symptoms: blood pressure variations (postural, postprandial), dysrhythmias |
Risk factors
Genetic factors5,6
- Mutations in the PTEN-induced kinase 1 (PINK1) and PARKIN6
Loss of function of these genes leads to impaired mitophagy, resulting in the accumulation of dysfunctional mitochondria.6 - Mutations in the DJ-16
DJ-1 has antioxidant effects through multiple mechanisms, loss of this gene also cause autosomal recessive early-onset PD.6 - Mutations in the GBA1 gene6
Carriers of a GBA mutation have an approximately 4-fold increased risk of PD. PD-linked GBA mutations cause a loss of activity of the lysosomal enzyme glucocerebrosidase.6 - Mutant leucine rich repeat kinase 2 (LRRK2)5
Mutant LRRK2 interferes with autophagy and has been reported to slow α-synuclein degradation, contributing to its accumulation.5 - Mutations of ATP132A5
ATP132A mutations determine lysosomal dysfunction and cause a young-onset parkinsonism.5
Toxicant chemical exposure6
- Pesticides such as paraquat, rotenone, 2,4-D and several dithiocarbamates and organochlorines, passive exposure to pesticide treated fields is associated with a greater risk of PD.6
- Chlorinated solvents (trichloroethylene, perchloroethylene, carbon tetrachloride), used in dry cleaning, degreasing, as an anesthetic and viscose rayon manufacturing and polychlorinated biphenyls, formerly used as coolants and lubricants, have also been associated with increased PD risk in humans and cause parkinsonism-associated toxicity in animal models.6
Other risk factors6
- Neuroinflammation might be and essential upstream contributor to α-synuclein aggregation and to the neurodegenerative process.6
- Epidemiological studies have provided evidence of associations between diseases with peripheral inflammation (e.g. type 2 diabetes and inflammatory bowel disease) and elevated PD risk.6
Footnotes:
-
LRRK1, leucine rich repeat kinase 2; NHI, National Health Insurance; NHIRD, Taiwan National Health Insurance Research Database; PD, Parkinson's disease; PINK-1, PTEN-induced kinase 1.
References:
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Hayes MT. Am J Med, 2019;132(7):802-807.
-
Reich SG, Savitt JM, Med Clin North Am, 2019;103(2):337-350.
-
Chaudhuri KR, Titova N. European Neurological Review, 2019;14(1):28–35.
-
Dorsey ER, et al. The Lancet Neurology, 2018;17(11): 939-953.
-
Balestrino R, Schapira AHV. Eur J Neurol, 2020;27(1): 27-42.
-
Simon DK, et al. Clin Geriatr Med, 2020;36(1): 1-12.
-
Liu CC, et al. Parkinsons Dis, 2016;2016:8756359.
-
Center for Parkinson and Movement Disorders, NTUH. http://www.pdcenterntuh.org.tw/ContentAspx/Browser00.aspx?. Accessed 25 Aug 2021.
-
Taiwan Clinical Oncology Research Foundation. http://web.tccf.org.tw/lib/addon.php?act=post&id=4500 Accessed 25 Aug 2021.
-
Armstrong MJ, Okun MS. JAMA 2020;323(6):548-560.
-
Galvan A, Wichmann T. Clin Neurophysiol, 2008;119(7):1459-74.