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.

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.

A New Conceptual Model for Understanding Parkinson’s Disease

1 Dorsey E.R.

Bloem B.R. The Parkinson pandemic — a call to action. 2 Espay A.J.

et al. Precision medicine for disease modification in Parkinson disease. 3 Espay A.J.

et al. Biomarker-driven phenotyping in Parkinson's disease: a translational missing link in disease-modifying clinical trials. A crucial unmet need for patients with Parkinson’s disease (PD) is a disease-modifying therapy. This is particularly urgent considering that the number of people with PD is set to double over the next 20 years, with over 14 million PD cases expected worldwide by 2040 []. We believe that an inadequate understanding of the relative relationship and temporal sequence of factors involved in PD pathogenesis might be hampering advances of new therapies. Many past attempts to develop therapies were designed with the aim of slowing disease progression by targeting single molecular pathways in PD pathogenesis; these attempts also typically viewed PD as a uniform disease, and subsequently treated all patients with the same therapeutic regimen. The PD research field is now questioning the accuracy of considering PD as a single entity. Instead it has been suggested that PD is in fact an umbrella term given to a large cluster of disorders encompassing a range of clinical, epidemiological, molecular, neuropathological, and genetic subtypes []. We would argue that if research programs culminate in clinical trials that continue to target a single pathogenic mechanism in groups of patients defined by the broad clinical diagnosis of PD, they are unlikely to yield effective disease-modifying treatment. We agree with the view that PD patients are a heterogenous population and, at best, patients can be grouped into different clusters with certain shared characteristics. In this opinion piece, we hypothesize that in a given patient, or patient cluster, the prevailing pathological mechanism will change during the different phases of PD. Based on this hypothesis, we propose a new conceptual model for PD pathogenesis. From the treatment perspective, the proposed model implies that medical interventions need to be disease-stage specific and personalized to maximize the chances of modifying the course of the disease.

Specifically, our model first divides the factors that contribute to neurodegeneration into three categories: triggers, facilitators, and aggravators. Second, we argue that each of these factors play distinct roles at different stages of the disease. Triggers encompass factors that enable the initiation of the disease process. These are most prominent during the period of ‘prodromal PD’. However, triggers alone are, in most cases, insufficient for PD to develop, as they require the presence of ‘facilitators’ for the disease to spread to, and significantly impact, the central nervous system. We propose that this applies not only to idiopathic PD, but also to familial forms of PD, as no known genetic form has complete penetrance, and the onset of PD symptoms in the familial forms are known to occur over a wide age span. We acknowledge that familial cases have a greater contribution of genetic factors as a facilitator event, compared with idiopathic PD. Facilitators can also be factors that sensitize cells to the toxic effects of triggers and promote a neurodegenerative cascade that may involve the formation and/or seeding of pathogenic α-synuclein. It would be necessary for these facilitators to be present during the initial stages of the disease process, when α-synuclein pathology transitions to the midbrain after initially being confined to a small number of cells in peripheral locations in the nervous system (e.g., enteric nerves) or central ones (e.g., olfactory system). Finally, we suggest a third category of factors that contribute to PD pathogenesis. These are ‘aggravators’, which directly promote the neurodegenerative process by exacerbating the pathology and promoting the spread of the disease beyond the basal ganglia.