Characterizing the smoking–PD relationship and understanding its nature are of great scientific and clinical importance, yet few epidemiologic studies have had large sample sizes and sufficient smoking information to do so. In the Cancer Prevention Study II Nutrition cohort, Thacker et al.9
indicated that the number of cigarettes per day, years of smoking, pack-years of smoking, and years since cessation were each associated with PD risk in a dose-response manner, consistent with results from a larger pooled analysis of 11 US studies.10
Interestingly, both articles reported lower PD risk even among smokers who quit 2 decades before disease diagnosis. Further, in the Cancer Prevention Study II Nutrition cohort, the authors stated in the text that the association of PD with cigarettes per day lost its significance after adjusting for years of smoking, whereas the association between years of smoking and PD remained after adjusting for smoking intensity.
The large sample size and lifetime smoking data of the current study enabled us to examine the smoking–PD relationship in further detail. In addition to the significant dose-response relationships between various smoking indicators and PD risk, we showed that the duration and the recency of smoking were more important than smoking intensity in modulating PD risk. Among past smokers, the lowest risk of PD was observed for participants who smoked the longest or who had quit most recently. Further, the number of cigarettes smoked per day became irrelevant once adjusted for smoking duration or years since last smoking. Finally, a longer smoking duration or fewer years since quitting was generally associated with lower PD risk within strata of smoking intensity, whereas the reverse was not observed. Among current smokers, where there was little variation in smoking duration, the number of cigarettes smoked per day was not related to PD risk.
This study, consistent with previous ones,9,10
suggests that patients with PD were less likely than controls to develop habitual smoking in early life or they were able to quit earlier. Further, the overall epidemiologic evidence favors a causal relationship between smoking and PD over several alternatives. Suspicion that this association is related to higher mortality among PD smokers than PD nonsmokers cannot explain results from prospective cohorts,1,11,12
and previous studies found that PD smokers did not have a higher mortality than PD nonsmokers.13,14
Reverse causality also is an unlikely explanation because the current work, as well as 2 other recent studies,9,10
found lower PD risk even among smokers who had quit 2 decades ago. The other alternative hypothesis suggests that the association is explained either by confounding from common genetic factors or by a low novelty-seeking personality that underlies both avoidance of smoking and a higher PD risk. Genetic factors are unlikely to be a major confounder because smoking was associated with lower PD risk among genetically controlled twins.2,15
A link between a risk-adverse or low novelty-seeking personality and PD is primarily based on anecdotal clinical observations and case-control studies.16,17
Further, smoking was related to lower PD risk even after controlling for sensation-seeking score.18
Finally, recent findings on passive smoking,3
and secular changes in gender ratios on smoking and PD19
provide novel support for the hypothesis that smoking decreases PD risk.
The robust epidemiologic evidence on smoking and PD has led to experimental efforts to elucidate a biologic basis.20
The existing animal models, however, may not be mechanistically similar, or at best, capture only a minor aspect of the smoking–PD relationship.5
This may explain why nicotine has been found to be protective in some animal experiments, but not in others.20
Most animal PD models have focused on relatively short-term, high-dose protection against cellular damage from exogenous cytotoxicants. The acute pharmacologic effects of nicotine (e.g., effects on dopamine turnover or metabolism) make untangling experimental data difficult. Most importantly, results from the current study suggest a chronic long-term effect of tobacco chemicals that may saturate at a low daily dose. If this observation is confirmed, the high-dose, acute administration of tobacco chemicals in laboratory studies should possibly be eschewed for experiments based on low-dose and long-term administration.
These findings also have clinical implications as nicotine has been investigated as a neuroprotectant in clinical trials. Small trials using nicotine delivered via patch or chewing gum typically lasted from days to weeks and largely failed to show beneficial effects on PD.21–25
The current study suggests that years of smoking (and hence nicotine administration) may be needed for any reduction of PD risk. Further, preliminary epidemiologic studies have shown that smoking was not associated with lower PD mortality13,14
or slower clinical progression.26,27
Therefore, while it is crucial to understand the smoking–Parkinson relationship, the epidemiologic evidence to date lends little support for the clinical usefulness of nicotine or other cigarette-derived chemicals in PD treatment.
The major limitation of this study is its reliance on self-report for case identification, inevitably leading to diagnostic and reporting errors. We tried to limit the potential impact from this source by excluding from the analysis erroneous reports identified in the ongoing validation study. Further, by contacting patients' neurologists and conducting medical record review, we were able to confirm 88% of the cases whose medical information was available. Another limitation is that we did not have detailed information on the date at onset or date at diagnosis for all PD cases, and thus were unable to estimate the incidence of PD and to conduct time to event analysis. Further, measurement errors of exposure variables were also likely. It is possible that the years of smoking were more reliably recalled than smoking intensity, which might be partially responsible for our finding. The current analyses were limited to participants of the follow-up survey. Because preliminary epidemiologic data suggest that PD smokers and PD nonsmokers have a similar clinical course and mortality,13,14,26,27
this limitation was unlikely to introduce a substantial bias. Finally, to our knowledge, this is the first study that comprehensively examined the relative importance of smoking duration vs intensity in PD etiology; therefore, the validity and generalizability of this finding should be further examined in future investigations.
As nearly all smokers in this cohort started smoking in their late teens and early 20s, years of smoking and years since last smoking are highly correlated among past smokers. Therefore we were unable to rule out the possibility that our findings on years of smoking were actually due to years from cessation. For the same reason, we were unable to examine directly the potential effects of recent short-term high-dose smoking on PD among individuals who did not smoke in early life. Nonetheless, this large study showed that the duration of smoking was more important than its intensity in reducing PD risk. Although the numerous adverse health effects of cigarette smoking may eventually limit the clinical implications of the epidemiologic findings on smoking and PD, research to reveal the underlying chemicals and mechanisms are warranted.