Perspective: Current Pitfalls in the Search for Future Treatments and Prevention of Parkinson's Disease

Abstract

We are gradually becoming aware that there is more to Parkinson's disease (PD) than meets the eye. Accumulating evidence has unveiled a disease complexity that has not (yet) been incorporated into ongoing efforts aimed at slowing, halting or reversing the course of PD, likely underlying their lack of success. There is a substantial latency between the actual onset of PD pathology and our ability to confirm diagnosis, during which accumulating structural and functional damage might be too advanced for effective modification or protection. Identification at the earliest stages of the disease course in the absence of Parkinsonism is crucial if we are to intervene when it matters most. Prognostic and therapeutic inferences can only be successful if we are able to accurately predict who is at risk for developing PD and if we can differentiate amongst the considerable clinicopathologic diversity. Biomarkers can greatly improve our identification and differentiation abilities if we are able to disentangle cause and effect.

Keywords: Parkinson's disease; biomarker; complex syndrome; disease modification; pre-diagnostic period.

Figure 1

The PD continuum with an extended disease course that includes a combination of risk factors that can pre-dispose or cause PD (0); a preclinical phase, where the pathology has started but no signs are present; a prodromal phase, where non-motor symptoms dominate, but motor symptoms can be present; and the classic or clinical phase often viewed through a dopaminergic lens, delineated by the clinical diagnosis (1) and mortality (2), with Levodopa therapy and/or deep brain stimulation (DBS) forming essential therapies for symptomatic management. Several risk factors (like age and lifestyle) also have the potential to affect disease progression. The Braak six-point staging scheme (A) spans across the entire PD continuum, while the Hoehn & Yahr symptom progression scale, for reference (B), is confined to the classic PD phase. Different biomarkers are better suited at different points along the continuum depending on pathological and clinical evidence.