The etiology of Parkinson's disease (PD) has long been discussed since the original description by James Parkinson.1 Parkinson mentioned that chronic injury to the cervical cord might be the cause of this disease because the disease often started in the upper extremities. But he did not make any definite statement on the etiology and pathogenesis of the disease.
As parkinsonism was the frequent sequel of Von Economo's encephalitis, virus infection was once postulated as a cause of nigral degeneration in PD. Von Economo's encephalitis started with the epidemics in Vienna in 1916,2 and resulted in worldwide pandemics until 1926, with a high morbidity of up to 80%.3 The incidence of parkinsonism among recovered patients was up to 80%, or more by the tenth year after the acute episode of encephalitis.4 The pathologic hallmark of postencephalitic parkinsonism is the presence of Alzheimer's neurofibrillary tangles in the remaining neurons in the substantia nigra (SN).5 It is unlikely that Von Economo's encephalitis or other viral infections play any etiologic role in the pathogenesis of PD.3
Another possibility that was once postulated is chronic metal intoxication. Chronic manganese intoxication produces parkinsonism,6,7 and the manganese and aluminum contents of water consumed by Guamanian people who developed parkinsonism–dementia complex were high.8 However, the clinical pictures of chronic manganese intoxication are different from those of PD.6 Pathologic changes are most prominent in the internal segment of the globus pallidus and subthalamic nucleus.9 Furthermore, brain manganese level is not elevated in PD.10
Recently, high incidence of parkinsonism among welders was reported in the United States.11 On the other hand, in a Swedish cohort study on welders did not prove higher incidence of parkinsonism and other movement disorders compared to general population.12 It is unlikely that chronic manganese exposure represents one of the etiologic factors for PD.13
The modern era started with the discovery of the specific nigral neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since then, many PD specialists believe that nigral neuronal death is initiated by the interaction of environmental neurotoxins and genetic predisposition. Such interaction is likely to induce mitochondrial dysfunction and oxidative stress; furthermore, mitochondrial dysfunction and oxidative stress can induce dysfunctions of the 26S proteasome and the autophagy–lysosome system inducing accumulation of toxic, misfolded, and aggregated proteins, particularly of aggregated α-synuclein.
Today, many etiologic and pathogenetic factors are postulated in PD. Etiology denotes a cause of the disease, whatever the mechanism of neurodegeneration may be, and pathogenesis represents molecular mechanisms that lead neurons to death (Fig. 12–1). Studies on genetic forms of PD contributed a great deal to the understanding of etiology and pathogenesis of sporadic PD. Genetics of PD is discussed in Chapter 9 of this textbook. In this chapter, we mainly discuss etiologic factors of ...