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Researchers suggest smoking may reduce risk of Parkinson's disease related death, and for those who smoked longer the risk was even less.

A six-decade follow-up study of nearly 30,000 British male doctors found that those who smoked tobacco when the study began in 1951 had a 30 percent lower risk of death from Parkinson's disease (PD), while those who continued to smoke had 40 percent lower risk, according to a report published in the May 5 online edition of Neurology.

The cohort study, which was followed up for 65-years, does not prove cause and effectthat smoking tobacco protects against PDbut it adds to previous findings that suggest that tobacco smoking is beneficial when it comes to the risk of developing PD. Researchers suspect that the nicotine found in tobacco may have a protective effect.

The researchers were careful to point out that the study should not be seen as advocating for smoking. Rather, they said that there needs to be a better understanding of why smoking may reduce the risk of PD because that might help explain the causes of the disease.

Current smoking is the leading cause of premature death and disability worldwide, and any such hazards would greatly exceed any beneficial effects of smoking on risk of Parkinson's disease, said study coauthor Robert Clarke, MD, professor of epidemiology and public health medicine at the University of Oxford, in an email to Neurology Today.

Little is known about the modifiable risk factors for PD, but previous studies have reported positive associations of PD with head injury, pesticide exposure, and consumption of dairy products, and inverse associations with caffeine, serum urate, physical activity, ibuprofen, and tobacco smoking, the study authors wrote.

The authors noted that a 2015 meta-analysis of observational studies reported that current smoking was associated with 60 percent lower risk of PD, but cautioned there is substantial uncertainty about the causal relevance of this inverse association. On the other hand, the authors cited a 2014 large case-control study from Denmark that suggested that the lower risk of PD in current smokers may be due to reverse causality bias, whereby early non-motor signs of PD may include a reduced response to nicotine stimulation, prompting current smokers to quit smoking before the diagnosis of PD can be made.

The current study, led by Benjamin Mappin-Kasirer, MSc, used data collected for the British Doctors Study, a prospective cohort begun in 1951 by Sir Richard Doll to examine the effects of tobacco smoking on disease-specific mortality. The study, which started with more than 34,000 doctors, was one of the first to establish the link between smoking and lung cancer.

The doctors who participated filled out a short questionnaire on their smoking status (current, ex, or never), amount smoked and in what form (cigarette, pipe or cigar). Ex-smokers were asked the questions about the time when they did smoke and about when they quit smoking.

Surviving participants were resurveyed by mail about changes in their smoking habits on six occasions between 1958 and 1998. The researchers collected cause-specific mortality for the doctors through November 20, 2016, using national mortality registries and personal inquiries. Complete mortality information was available for 99 percent of the study participants. The long follow-up period of the study coincided with a time when cigarette smoking was declining in the British population. Among doctors aged 65 to 69, the prevalence of current smoking declined from 67 perceny in 1951 to 8 percent in 1998, the study said.

The new analysis was based on information on 29,737 doctors. There were 25.879 deaths in the group, including 283 deaths that listed PD as the underlying cause. The average age of PD death was 82 years. The unadjusted rates of PD death were lower in current smokers (30 deaths per 100,000 person-years) compared with those who never smoked at baseline (46 deaths per 100,000 person- years). After the researchers did statistical adjustments for age-at-risk, current smokers at baseline had a 30 percent lower risk of PD, and the current smokers (classified as such using updated smoking habits on sequential resurveys) had a 40 percent lower risk of PD compared with doctors who never smoked.

The risks of PD were inversely associated with the amount of tobacco smoked, the researchers reported. Also, the protective effect of current smoking versus never smoking for PD was attenuated by increasing duration since quitting smoking.

Current smoking is the leading cause of premature death and disability worldwide, and any such hazards would greatly exceed any beneficial effects of smoking on risk of Parkinson's disease.

DR. ROBERT CLARKE

The investigators concluded in contrast with previous suggestions, the present report demonstrates a causally protective effect of current smoking on risk of PD.

Dr. Clarke said that while more needs to be learned, the most likely explanation is that the nicotine content in tobacco smoke may have protective properties, possibly by stimulating the release of dopamine, but the effects of other components of tobacco cannot be excluded.

The researchers said the strengths of their study included its large size and lengthy follow-up, a high response rate to the repeated surveys, and the fact that they used several statistical models to account for changes in smoking habits, reverse causality, and age-at-risk of PDeach of which yielded consistent results.

Limitations included the fact that there were only 283 PD cases, participants were all male British doctors, and the surveys did not collect information on family history, caffeine intake or other factors.

Rodolfo Savica, MD, PhD, associate professor of neurology and epidemiology at the Mayo Clinic in Rochester, MN, said the new analysis on smoking and PD is another piece of the puzzle. There is something there, but what is not yet clear.

He said that while nicotine is often singled out, we don't know if it's nicotine. He said that some of the studies using nicotine did not yield any results in Parkinson's disease, and did not find a protective effect.

Dr. Savica, who conducts PD research, said the all-male cohort in the British study makes him question what the effect of smoking tobacco would be on a similarly large study of women, noting that Parkinson's disease can present differently in men and women. Dr. Savica was the lead author on a study published in 2016 in JAMA Neurology that found an increase in PD from 1976 to 2005. The 30-year trend was derived from data collected for the Rochester Epidemiology Project. While the study was unable to conclude why there was an increase in cases, particularly among older men, environmental changes, including less smoking, was suggested as a possible factor.

Dr. Savica said cohort studies need to be interpreted with caution. As a physician it would be criminal for me to say to my patients, Start smoking now. They would die of cancer, he said.

Susan Searles Nielsen, PhD, assistant professor of neurology and a neuroepidemiologist at Washington University in St. Louis, said the inverse association between tobacco smoking and risk of Parkinson's has been strong and very consistent in the medical literature. But she said she does not agree with the Oxford researchers that their findings clearly indicate a causally protective effect, and likewise does not believe cause-and-effect can yet be ascribed to previous such findings.

Dr. Nielsen said that although this and other studies have consistently found a protective effect of tobacco, a very plausible alternative [hypothesis] remains that individuals predisposed to PD might have a different response to nicotine that extends back as far as adolescence, when smoking typically begins.

She said smoking tobacco could, with further study, turn out to be causal, non-causal or a bit of both, in terms of risk for PD. She said a few epidemiologic studies, including one that she coauthored, have found an association between exposure to second-hand tobacco smoke and lower risk of PD.

We don't know what it is about tobacco that might decrease the risk of Parkinson's disease if the association does turn out to be causal, Dr. Nielsen said. She noted that when people smoke tobacco, there is a massive host of other chemicals that come along with the nicotine.

To test the nicotine theory, she conducted a study that collected information on the past dietary habits of newly diagnosed PD patients and non-PD controls to examine whether nicotine-containing edibles from the same botanical family as tobacco might provide any protective effect. The study, published in Annals of Neurology in 2013, suggested that eating nicotine-containing foods, particularly peppers, might be protective against PD, Dr. Nielsen said.

Iris Kim, ScD, a senior epidemiologist at Vertex Pharmaceuticals in Boston (who did post-doctoral research at the Big Data Institute of Oxford University, but did not work on this study), said the new study is noteworthy.

That the follow-up period is so long is the major strength of the study, she said, as well as the fact that it corroborates previous findings that smoking is protective. Dr. Kim said one shortcoming of the study was that it did not collect information on caffeine intake, and so authors could not take into account the participants' caffeine intake, which has been shown to be protective against PD in some studies.

Dr. Kim last year published a large cohort study of 1.3 million women in the United Kingdom that found no association between alcohol intake and PD risk, and another study in 2013 that reported that caffeine intake was associated with a lower risk of Parkinson's disease among men. Both papers were published in Movement Disorders.

She said she agreed with the British researchers that the mechanism through which smoking may be protective are not fully understood. What are the biological agents that are driving this?

Drs. Clarke, Nielsen, and Savica had no disclosures.

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