Demographic Factors Increasing age Male gender White race
Family history of Parkinson's disease
Personality traits (shyness, risk averse) Environmental Exposures
MPTP and MPTP like compounds
Metals (manganese, mercury, iron)
Drinking well water
Occupation (health care, teaching, construction work) Infections Encephalitis Nocardia asteroides
In case-control studies, persons with Parkinson's disease consistently report more affected family members than do controls.55,56 However, biased recall has been found to contribute to this in at least one study in which reported history was verified by an examination.57 Twin studies may also provide clues to the relative contribution of genetic factors to the cause of disease. If the cause of a disease were primarily genetic, then the rate of disease in monozygotic (MZ) twins would be greater than that in dizygotic (DZ) twins. Twin studies of Parkinson's disease have failed to support a major genetic effect. A recent large, population based twin study of 163 pairs showed similar rates of concordance in MZ and DZ twin pairs.58 Two small follow-up studies had contradictory results, one finding increased MZ concordance and the other failing to find a difference in MZ and DZ concordance.59,60 A prospective follow-up of the population-based cohort is now under way.
While genetic causes do not appear to be primary in typical, sporadic Parkinson's disease, investigating the mechanisms underlying the genetic causes of parkin-sonism can provide important clues to the common patho-genesis of all parkinsonism. The relative paucity of evidence supporting a genetic cause for typical Parkinson's disease has sparked interest in investigating environmental risk factors for Parkinson's disease.
In the early 1980s, interest in environmental causes of Parkinson's disease was ignited by the description of a cluster of parkinsonism produced by the neurotoxic pyri-dine,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a relatively simple pyridine compound that induces most if not all of the features of Parkinson's disease in humans61 and experimental animals.6263 While MPTP is rare outside of the laboratory, related chemicals more commonly present in the environment were proposed as possible causes of Parkinson's disease. Subsequently, case-control studies have investigated and suggested numerous associations between environmental exposures and Parkinson's disease (Table 5.3). These specific environmental toxins and associations are mentioned here briefly and will be discussed in detail in later chapters.
Because MPTP resembles the herbicide paraquat, and several ecologic studies suggested a rural preponderance of Parkinson's disease, factors associated with the rural environment have been studied. Multiple case-control studies have detected positive associations between Parkinson's disease and exposure to pesticides,64-66 well water,67-69 and rural living.67,69 Information about exposures to specific agents is limited but suggests paraquat,70 dieldrin,71 organochlorines,64 alkylated phosphates,64 and carbamate derivatives65 may have a causal role in Parkinson's disease. In China, several decades ago, a case-control study found that exposure to industrial chemicals, printing plants, or quarries was associated with an increased risk of developing Parkinson's disease but found no relationship with agricultural work and Parkinson's disease.72 In contrast, an investigation in Hong Kong during that time period did find such an association,73 perhaps due to differences in farming practices or other environmental factors between the less developed mainland and the more developed island of Hong Kong at that time. Individual studies have had conflicting results, possibly due to methodological differences, small samples, and regional differences in farming practices or differences in population characteristics.
Occupational exposures and risk of Parkinson's disease has been investigated in a small number of studies. Several of these studies have shown associations of Parkinson's disease with industries using metals,74 although results of studies of specific metals have been inconsis-tent.75 Occupational exposures to metals suggested a positive association between exposure to manganese and mercury.75 In addition to occupational exposures to pesticides and metals, a higher frequency of Parkinson's disease has been reported among teachers,76 health workers,76 construction workers,77 carpenters, and clean-ers.78 The clues to the etiology of Parkinson's disease gathered by these associations will be explored in detail in later chapters.
The association between head trauma and Parkinson's disease has been investigated in many case-control studies. The overall epidemiological evidence in favor of or against the role of head trauma in Parkinson's disease remains controversial. Several studies reported a positive association between head trauma and Parkinson's disease risk,6479-81 while others have found no relation between head trauma and Parkinson's disease risk.6882-84 Because most studies have relied on the report of the person with Parkinson's disease or a control, biased recall has been a concern. In a recent population-based study in Olmstead County, Minnesota, head trauma documented in the medical record was associated with an increased risk of Parkinson's disease, although this association was restricted to more severe head trauma. Head trauma could be a direct causal factor triggering or predisposing to factors causing loss of nigral neurons. Alternatively, head trauma could be a reflection of early motor problems in preclinical Parkinson's disease,85 although in some studies the trauma preceded the onset of Parkinson's disease by many decades, making this less plausible.
Parkinsonism was a sequela in the survivors of the 1917 to 1935 epidemic encephalitis, resulting in the proposal that all Parkinson's disease was the result of this infection. This belief persisted, despite the fact that pos-tencephalitic disease and Parkinson's disease have clear differences both clinically and pathologically,86 until it was laid to rest when disease rates did not decrease despite the lack of exposed persons in the population. To date, an infectious agent has never been shown to cause typical Parkinson's disease. The soil pathogen Nocardia asteroides causes a levodopa responsive movement disorder and nigral degeneration in mice.87 However, a serologic case-control study in humans did not support a role for Nocardia asteroides in Parkinson's disease.88 Several case-control studies found an association between occupations thought to be associated with an increased risk of infection, such as teaching and health care.89 90 Because inflammatory processes appear to contribute to nerve cell death in Parkinson's disease, investigating the role of infectious agents remains interesting, but challenging.
Factors proposed to protect against the development of Parkinson's disease include cigarette smoking, coffee consumption, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Of these, the most compelling is the inverse association of cigarette smoking with Parkinson's disease risk seen in both case-control and prospective studies,6470 83 91-98 with multiple studies confirming an inverse dose-response pattern with regard to cumulative lifetime cigarette smoking.9699100 Although not all studies confirmed the inverse association,101102 and a clearly defined biological basis for this finding has yet to be defined. One hypothesis is that smoking protects against the development of Parkinson's disease because of its effect on the enzyme monoamine oxidase (MAO) B. Cigarette smoke reduces MAO B activity in the animal and human brain.103 104 MAO B activates the neurotoxin MPTP, and a MAO B inhibitor, cigarette smoke, may offer neuroprotection in Parkinson's disease.61,105 Another hypothesis is that nicotine itself is neuroprotective,92 given that it has antioxidant properties.106 The nicotine in cigarette smoke may inhibit free radical formation and offer associated neuronal protection. An alternative hypothesis is that some inherent, perhaps life-long characteristic of those destined to develop Parkinson's disease also determines a constitutional lack of interest in smoking cigarettes. The relationship between dopaminergic systems and addiction lends some credence to this proposal. Evidence against an inborn "low dopamine" state is provided by the observation that an inverse effect of smoking and Parkinson's disease risk is seen in monozygotic twin pairs, one of whom has Parkinson's disease.92 There are overwhelming health risks associated with cigarette smoking, and this behavior should be avoided. Nonetheless, the evidence that smoking is somehow protective is intriguing, and delineation of the underlying biochemical mechanism could lead not only to insights into the cause of the disease but perhaps also to useful and safe preventive approaches.
Coffee drinking or caffeine intake is a second behavior inversely associated with the risk of Parkinson's disease.93,97,107109 In the most methodologically compelling study, a dose-dependent reduction in Parkinson's disease risk was observed in a prospective cohort of men.108 But further investigation of this effect will be needed, as caffeine may not affect all persons similarly. For example, Ascherio et al. reported an interesting difference among women—that caffeine reduces the risk of Parkinson's disease among women who do not use postmenopausal hormones, but it increases risk among hormone users.110 As a result, there was not a clear overall relationship between caffeine or coffee intake and Parkinson's disease in this cohort. The latter findings suggest a potential interaction between caffeine consumption and estrogen exposure in mediating Parkinson's disease risk. An investigation of the actions of caffeine in the brain provides some plausibility for the possibility that caffeine my alter disease risk. The biologic effects of caffeine are mediated in part through its antagonist action on the adenosine A2 receptor, which in turn modulates dopaminergic neurotransmission111,112 and protects against striatal dopamine loss caused by MPTP in laboratory studies.113115
Glial cell-mediated inflammation may contribute to the nigralstriatal degeneration found in Parkinson's disease. Studies of Alzheimer's have shown that the regular use of NSAIDs may reduce the risk of Alzheimer's in humans.116,117 Since Alzheimer's and Parkinson's disease share common pathogenic mechanisms of neuronal cell death and degeneration, investigations have looked at the use of NSAIDs and the risk of Parkinson's disease. The regular use of nonaspirin NSAIDs was associated with a 45% lower risk of Parkinson's disease in a prospective study of men and women suggesting neuroprotective effects of NSAIDs.118 This was also the second prospective study to find that aspirin use was associated with a lower incidence of Parkinson's disease.118,119 Although current evidence is compelling, it will be important for future studies to determine the specific compounds and mechanisms that may mediate the protective effects of smoking, coffee drinking, and NSAIDs use.
Alcohol has been found by some to be inversely associated with Parkinson's disease in a few prospective studies,99,109,120 although the associations were of borderline significance. There is a great deal of variability across studies and the inverse association between alcohol and Parkinson's disease is weak in studies to date. Other protective factors associated with Parkinson's disease have been identified in single studies but not replicated to date. These include early childhood measles infection121 and early or mid-life exercise.122
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