Does This New Clue Explain the Smoking-Parkinson’s Mystery?

Carbon monoxide (CO) may help explain the long-observed, but perplexing, association between cigarette smoking and a lower risk for Parkinson’s disease (PD).Results of a large, observational study showed higher exhaled CO levels were associated with a lower risk for PD not only in smokers as well as never-smokers, supporting the possibility that the inverse association between smoking and PD may not be attributable to tobacco smoking itself.“This is the first study to provide robust evidence in humans of a lower risk of Parkinson’s associated with higher levels of exhaled CO,” study investigators, Clara Bueno Lopez, MSc, and Fiona Bragg, DPhil, with Nuffield Department of Population Health, University of Oxford, Oxford, England, noted in an email to Medscape Medical News.“These findings provide support for on-going clinical trials of low-dose CO as a potential therapeutic intervention in Parkinson’s; if successful this could contribute to substantially reducing the global burden of Parkinson’s,” they added.The study was published online on September 8 in JAMA Neurology.Dose-Dependent LinkSmoking has long been associated with a lower risk for PD, often with dose-response relationships involving smoking intensity and duration. Nicotine has been proposed as one potential explanation. However, a randomized trial of transdermal nicotine in patients with early PD failed to slow disease progression.One alternative candidate is CO. Although high levels of the gas are toxic, CO is also produced naturally in the body and acts as an essential signaling molecule involved in responses to oxidative stress, inflammation, and cell survival. At low concentrations, CO has shown neuroprotective effects in laboratory and animal studies, including preclinical models of PD.For the study researchers analyzed data from 512,701 adults who reported their smoking history and underwent standardized measurement of exhaled CO at baseline between 2004 and 2008. Their mean age at baseline was 52 years, and 59% were women.On average, exhaled CO levels were substantially higher among regular smokers (11.1 parts per million) than among never-smokers (3.5 ppm), occasional smokers (3.8 ppm), and former regular smokers (3.7 ppm).Over a median follow-up of about 12 years, 1131 participants developed PD and 2949 developed other neurodegenerative diseases.As expected, regular smokers had significantly increased risk for lung cancer, ischemic heart disease, stroke, and all-cause mortality but a lower risk for PD (hazard ratio [HR], 0.70).Among never-smokers, higher exhaled CO levels were also associated with lower risk for PD in a broadly dose-dependent manner.Relative to the lowest exhaled CO quintile (< 2 ppm), never-smokers in the highest quintile (≥ 11.5 ppm) had a 35% lower risk for PD (HR, 0.65). Risk was 15% lower at CO levels of 2 to < 3 ppm (HR, 0.85), 38% lower at 3 to < 5 ppm (HR, 0.62), and 32% lower at 5 to < 11.5 ppm (HR, 0.68).The inverse association appeared relatively specific to PD. Exhaled CO levels among never-smokers were not associated with other neurodegenerative diseases or smoking-related diseases.Promising Clue, Replication NeededIn a statement from the UK nonprofit Science Media Center, Toni Pitcher, PhD, senior research fellow in PD epidemiology at the University of Otago, Christchurch, New Zealand, noted that the “so-called protective effects of cigarette smoking on risk of PD has sat uncomfortably with the medical community since it was first described in 1959. Surprisingly, the exact mechanism underlying this association remains elusive.”Pitcher said the findings point to CO as one potential mediator of the smoking-PD association.“The challenge now is to replicate these findings in independent cohorts and to better understand how carbon monoxide counteracts the pathology associated with Parkinson’s,” she noted.Whether CO could benefit patients — and which patients might respond — remains uncertain, Pitcher said.The co-authors of a linked editorial questioned whether relatively small differences in exhaled CO — for example, from < 2 ppm to 3-5 ppm — could plausibly reduce PD risk by more than 30%.Sirwan K.L. Darweesh, MD, PhD, of Radboud University Medical Center, Nijmegen, Netherlands, and co-authors noted that exhaled CO measurements can vary with environmental exposure, breathing patterns, recent food intake, and time of day, which adds uncertainty about the biological meaning of relatively small differences in measured CO.Nonetheless, they said the findings add “compelling additional weight to the scales for CO” and help “set the agenda for future research” aimed at establishing causality and potential neuroprotection.An ongoing phase 2a randomized, placebo-controlled trial is evaluating the safety, tolerability, pharmacokinetics, and mechanistic effects of a low-dose oral CO intervention in those with PD.The study had no commercial funding. Disclosures for the authors are available with the original study publication. Pitcher and Darweesh had no relevant conflicts of interest.