Epidemiological Factors – General Considerations

Controversy over the etiology and pathogenesis of Parkinson’s disease (PD) has continued for many years and while the details have changed, the uncertainty persists. Although heritability was most emphatically refuted a decade ago by many investigators, recent progress firmly indicates that genetic factors at least play a role, although probably to a variable degree from one individual to another. Evidence for a variety of other etiological factors is amassed from epidemiological studies, animal models, molecular and cellular biology. Genetic factors, infectious and immunological abnormalities, the effects of ageing, toxins (endogenous as well as exogenous) and other environmental factors may all contribute to the development of PD. Loss of nigral dopaminergic neurons may be mediated by varying combinations of oxidative free radical toxicity, impaired mitochondrial function, “weak excitotoxicity” and abnormal handling of cytoskeletal proteins, all of which may shift the balance regulating apoptotic cell death. RÉSUMÉ: Étiologie de la maladie de Parkinson. La controverse entourant l’étiologie et la pathogenèse de la maladie de Parkinson (MP) dure depuis plusieurs années et, bien que les détails ont changé, l’incertitude persiste. Bien que l’héritabilité de la maladie ait été réfutée avec emphase par plusieurs investigateurs il y a une dizaine d’années, des progrès récents indiquent clairement que des facteurs génétiques sont en cause, probablement à des degrés variables d’un individu à l’autre. Des données sur une variété d’autres facteurs étiologiques, provenant d’études épidémiologiques, de modèles animaux, de la biologie moléculaire et cellulaire, s’accumulent. Les facteurs génétiques, anomalies infectieuses et immunologiques, les effets du vieillissement, les toxines (endogènes et exogènes) et les autres facteurs environnementaux peuvent contribuer au développement de la MP. La perte de neurones dopaminergiques dans la substance noire peut être médiée par différentes combinaisons d’effets toxiques oxydatifs dus à des radicaux libres, une fonction mitochondriale altérée, une “faible excitotoxicité” et un métabolisme anormal des protéines du cytosquelette, qui peuvent tous déséquilibrer la régulation de la mort cellulaire par apoptose. Can. J. Neurol. Sci. 1999; 26: Suppl. 2-S5-S12 From the Neurodegenerative Disorders Centre, Vancouver Hospital & Health Sciences Centre, Vancouver, British Columbia. Reprint requests to: A Jon Stoessl, Neurodegenerative Disorders Centre, Faculty of Medicine, Vancouver Hospital & Health Sciences Centre, Purdy Pavilion, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5 https://doi.org/10.1017/S0317167100000032 Downloaded from https:/www.cambridge.org/core. IP address: 54.191.40.80, on 31 Mar 2017 at 07:23:18, subject to the Cambridge Core terms of use, available at https:/www.cambridge.org/core/terms. disease onset prior to the age of 50, suggesting that genetic factors may play a greater role in disease of earlier onset. There is an increased incidence of family history of Parkinson’s in affected individuals (16% vs. 4% in controls; age-adjusted odds ratio 3.5), which may not entirely reflect genetic factors. Families with a dominantly inherited condition which is pathologically indistinguishable from PD and clinically similar have been identified, but most investigators consider these to be special cases. This includes the recently described association of familial parkinsonism with a mutation (Ala53Thr) of the gene encoding α-synuclein in the Contursi kindred, where the age of onset is younger than average, tremor is less frequent and progression is more rapid. Although this mutation was also found in other families, they were all of Greek or Sicilian origin, raising the possibility of a founder effect. A different (Ala30Pro) mutation in this gene has been described in a German family with parkinsonism. The α-synuclein mutation has now been excluded in numerous other families with dominantly inherited parkinsonism, as well as pathologically verified sporadic PD. Linkage in one family has recently been demonstrated to the short arm of the 2nd chromosome. Despite the recent interest in mitochondrial abnormalities (see below), there has been no convincing evidence of maternal transmission or mitochondrial DNA abnormalities in PD, although analysis of cytoplasmic hybrids (cybrids) suggests that the abnormality of Complex I is indeed derived from mitochondrial DNA. While juvenile parkinsonism is linked to a region of the long arm of the 6th chromosome, where mitochondrial (Mn) superoxide dismutase (SOD2) is encoded, SOD2 expression was high in a single patient with this disorder and the mutation has recently been identified in a gene called parkin. The N-terminal sequence of Parkin is similar to the ubiquitin family of proteins and it is therefore possible that juvenile parkinsonism results from impaired proteolytic processing. The importance of this mechanism is further supported by the recent identification of an Ile93Met mutation of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene in a German pedigree with typical, adult-onset parkinsonism. Genetically inherited susceptibility to certain toxins has been suggested by diminished debrisoquine hydroxylation, sulfoxidation and S-methylation reactions. An increased incidence of mutant alleles of the CYP2D6 gene has been reported by multiple groups, but this does not seem to segregate with disease expression within families with multiple affected members. Similarly, reports that PD may be associated with increased frequency of an MAO-B allele have not been consistently reproduced. A number of other candidate genes (GPX1, TH, BDNF, CAT, APP and SOD1, as well as CYP2D6) have been excluded in at least some families. NATURE VS. NURTURE – POPULATION STUDIES Although PD is in general widespread, some populations seem to have a lower incidence. This would include South African and Nigerian blacks, although blacks living in Mississippi are affected to a comparable degree as the white population and a recent autopsy study suggests that black Africans have an equivalent prevalence of incidental Lewy body disease. Lower incidences have likewise been reported in Oriental populations (but not in Oriental Americans and possibly not in Taiwanese). While many investigators have reported an increased risk of having a close relative with PD in patients compared to controls, one interesting study of families in which members of multiple generations were affected suggested that disease onset clustered around the same calendar year rather than a comparable chronological age, again suggesting shared exposure (and susceptibility?) to some unidentified environmental factor. Epidemiological studies have also led to more direct support for an environmental hypothesis. Young-onset parkinsonism has been associated in a number of studies with exposure to well water. No specific toxin has been identified and the well water link has not been found in all studies, although a more consistent factor seems to be rural upbringing. One compelling rural factor is pesticide/herbicide exposure, although this has also not been reproduced in all studies. The association may be strengthened by a recent post-mortem report of increased detection of the lipid-soluble pesticide (and mitochondrial toxin) dieldrin in the brains of Parkinson patients compared to Alzheimer and normal controls. While rural environments are associated with an increased risk of PD in the industrialized world, the opposite seems to be true in China, where exposure to industrial chemicals is less likely to occur in the countryside. In China, consumption of well water or high ethanol intake are associated with a reduced risk of Parkinson’s, whereas the risk is increased in those who consume river water or live in proximity to rubber plants. Data from the Canadian study on ageing recently suggested a relationship to plastic or epoxy resin exposure. 32 Numerous investigators have suggested an inverse relationship between smoking and Parkinson’s disease, but this finding has remained controversial and most of the reports were based on case-control studies. 3 3 6 Whereas a recent case-control study confirmed a lower prevalence of c u r r e n t smoking in Parkinsonians, but no difference in prior exposure (suggesting that there is no protective effect, but rather that PD itself leads to reduced smoki n g ) , 4 another p r o s p e c t i v e study of more than 8,000 men enrolled in the Honolulu Heart Program did indeed support a reduced risk of Parkinson’s in smokers or ex-smokers (relative risk = 0.39), with an apparent dose-response effect. 7 If the relationship is indeed a real one, there still exists the question of whether it reflects a “rigid” premorbid personality trait, as has been repeatedly described in PD, or a lower propensity to nicotine addiction, rather than a “protective” effect of smoking, perhaps mediated by stimulation of toxin-neutralizing enzymatic pathways. Some retrospective studies have found an increased risk of PD following head injury, but this has been quite variable. INFECTIOUS AND IMMUNOLOGIC MECHANISMS The pandemic of encephalitis lethargica in the early 20th century led to parkinsonism which was clinically and pathologically distinct from idiopathic disease, but there were nonetheless expectations that an infectious etiology might be found for the “idiopathic” disorder. Sporadic post-encephalitic parkinsonism does still occur, albeit very rarely, but repeated efforts to identify an infectious agent which is consistently associated with the development of PD have failed. Interest has been rekindled by the appearance of clinically typical parkinsonism in patients with encephalitis, with image evidence of damage confined to the THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES