Slowing or halting progression continues to be a major unmet medical need in Parkinson's disease (PD). Numerous trials over the past decades have tested a broad range of interventions without ultimate success. There are many potential reasons for this failure and much debate has focused on the need to test 'disease-modifying' candidate drugs in the earliest stages of disease. While generally accepted as a rational approach, it is also associated with significant challenges around the selection of trial populations as well as trial outcomes and durations. From a health care perspective, intervening even earlier and before at-risk subjects have gone on to develop overt clinical disease is at the heart of preventive medicine. Recent attempts to develop a framework for a biological definition of PD are aiming to enable 'preclinical' and subtype-specific diagnostic approaches. The present review addresses past efforts towards disease-modification, including drug targets and reasons for failure, as well as novel targets that are currently being explored in disease-modification trials in early established PD. The new biological definitions of PD may offer new opportunities to intervene even earlier. We critically discuss the potential and challenges around planning 'disease-prevention' trials in subjects with biologically defined 'preclinical' or prodromal PD.
Keywords: Parkinson’s disease (PD); biological definition of PD; disease-modification; disease-prevention; neuroprotection; preclinical PD; prodromal PD.