Triggers, Facilitators, and Aggravators: Redefining Parkinson's Disease Pathogenesis.

We hypothesize that Parkinson's disease (PD) pathogenesis can be divided into three temporal phases. During the first phase, 'triggers', such as viral infections or environmental toxins, spark the disease process in the brain and/or peripheral tissues. Triggers alone, however, may be insufficient, requiring 'facilitators' like peripheral inflammation for PD pathology to develop. Once the disease manifests, 'aggravators' spur further neurodegeneration and exacerbate symptoms. Aggravators are proposed to include impaired autophagy and cell-to-cell propagation of α-synuclein pathology. We believe clinical trials need to consider these three phases and target potential therapies at the appropriate stage of the disease process in order to be effective. Highlights We propose a new conceptual model for PD pathogenesis, in which disease-associated factors are divided into three categories: triggers, facilitators, and aggravators. Triggers are agents or events that begin the disease process; these factors are necessary but insufficient for PD to develop. Facilitators are factors that allow the disease to spread to, and significantly impact, the central nervous system. Aggravators directly promote the neurodegenerative process and often have a snowballing effect that exacerbates pathology and spreads the disease beyond the basal ganglia. We propose that clinical therapies aimed at slowing or arresting PD progression should not only be given to patients enriched for the appropriate target (i.e., administered to the appropriate subpopulation), but also be applied during the appropriate temporal phase at which the relevant factor is most active. [ABSTRACT FROM AUTHOR]