Background Several non-motor features may individually contribute to identify prodromal Parkinson’s disease (PD), but little is known on how they interact.
Methods We conducted a case–control study nested within the Health Professionals Follow-up Study in a large cohort of men age 40–75 at recruitment in 1986. Cases (n=120) had confirmed PD, were<85 in January 2012, returned a 2012 questionnaire with questions on probable rapid eye movement sleep behaviour disorder (RBD) and constipation sent to all cohort participants and completed in 2014 the Brief Smell Identification Test and a questionnaire assessing parkinsonism and other non-motor PD features (including depressive symptoms, excessive daytime sleepiness, impaired colour vision and body pain). Controls (n=6479) met the same criteria as cases, except for the PD diagnosis.
Results Concurrent constipation, probable RBD and hyposmia were present in 29.3% of cases and 1.1% of controls, yielding an age-adjusted OR of 160(95%CI 72.8to353) for three features versus none. The odds of PD increased exponentially with additional non-motor features (OR for 6–7 features versus none: 1325; 95%CI333to5279). Among men without PD, the number of non-motor features was associated with odds of parkinsonism (OR for 6–7 features versus none: 89; 95%CI21.2to375). We estimated that in a population with a prodromal PD prevalence of 2%, concurrent constipation, probable RBD and hyposmia would have a maximum sensitivity of 29% and a positive predictive value (PPV) of 35%. The PPV could increase up to 70% by including additional features, but with sharply decreased sensitivity.
Conclusions Concurrent constipation, probable RBD and hyposmia are strongly associated with PD. Because these features often precede motor symptoms and their co-occurrence could provide an efficient method for early PD identification.
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Contributors KCH, XG, JMB, CS, MAS and AA contributed to data acquisition. XG, MAS and AA contributed to study concept and design. KCH, LV and AA contributed to data analysis. KCH, XG, JMB, CS, IYK, LV, MAS and AA contributed to drafting the manuscript and figures.
Funding This study was supported by Department of Defense grant W81XWH-14-0131. The HPFS cohort is funded by NIH grant UM1 CA167552.
Competing interest XG has served on committees of the Sleep Research Society, American Academy of Sleep Medicine, and Parkinson Study Group and received funding from the NIH/NINDS. MAS served on the scientific advisory board for CBD Solutions (foundation), has served as a consultant for New Beta Innovation (company) and Harvard University and is funded by NIH grants NS090259, NS098746, U13NS103523, Department of Defense W81XWH-11-1-0150, the Michael J. Fox Foundation, the Parkinson’s Alliance, the Parkinson’s Foundation and Target ALS Foundation. AA received a research grant from the Department of Defense related to this work. He has also received research grants from the National Institutes of Health, the Michael J. Fox Foundation and the National Multiple Sclerosis Society, outside of this work.
Patient consent Not required.
Ethical approval Human Research committees at the Brigham and Women's Hospital and the Harvard T. H. Chan School of Public Health.
Provenance and peer review Not commissioned; externally peer reviewed.