Abstract
Despite recent successes in understanding the genetics of Parkinson's disease (PD), the causes of late-onset sporadic PD remain elusive. Many of the epidemiologic findings on PD etiology have been challenged by alternative explanations such as reverse causation. This is mainly because PD often takes decades to develop before it can be diagnosed late in life. Convincing evidence shows that this prodromal stage of PD is characterized by various prodromal symptoms such as olfactory impairment and rapid-eye-movement sleep behavior disorder (RBD). As they likely reflect PD pathogenesis years, if not decades, before nigrostriatal involvement, research on these symptoms may represent an unprecedented opportunity to dissect the etiology of PD. Using PD prodromal symptoms as intermediate phenotypes, we may be able to identify factors that contribute to the development of these symptoms and factors that modify their progression to clinical PD. Further, this line of research will also enable examinations of novel etiological hypotheses of PD development such as the microbiome and prion hypotheses. In this article, the author used olfactory impairment and RBD as examples to illustrate the promises and challenges of epidemiologic research on prodromal symptoms to understand PD etiology.