Research on the premotor symptoms of Parkinson's disease: clinical and etiological implications

Abstract

Background: The etiology and natural history of Parkinson's disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years.

Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications.

Methods: This review was based on a workshop, Parkinson's Disease Premotor Symptom Symposium, held 7-8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.

Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood.

Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis.

Figure 1

A hypothesis on the development of premotor symptoms among persons who will or will not develop PD in lifetime. The green lines represent the joint prevalence of multiple premotor symptoms by age; solid, future PD cases, and dashed for noncases. The red line represents motor signs among future PD patients. The blue line represents the loss of dopaminergic neurons in the substantia nigra pars compacta of PD patients which underlies cardinal motor signs. PD diagnosis is made based on cardinal motor signs (red) when approximately 50% of the dopaminergic neurons in the substantia nigra have been lost (threshold shown as the black dotted line). Individuals at high risk for PD (solid green line) will develop multiple premotor symptoms years before onset of PD motor signs; for individuals who will not develop PD (dashed green line), the joint prevalence of these symptoms remain at low level even at older age.

Figure 2

A hypothesis on risk factors, premotor symptoms, and PD. Environmental or genetic factors may initiate neurodegeneration through mechanisms such as neuroinflammation; in susceptible individuals, this may first lead to premotor symptoms years before PD clinical onset; if this neurodegeneration continues without effective intervention, premotor symptoms may eventually progress into overt PD; however, with interventions such as coffee drinking, this premotor progression may be halted before it becomes irreversible.