Figure 1.

Natural history of Parkinson's disease.

Patients with Parkinson's disease experience a long phase, which can last decades, characterized by sub-clinical symptoms in non-motor domains (with rapid eye movement sleep behavior disorders being the most reported). In this phase, it is hypothesized that neurons become dysfunctional, with alterations in neuronal and synaptic communications accounting for those sub-clinical signs. Importantly, persistent synaptic dysfunction can lead to neuronal demise and death. With the progression of the disease, patients will begin manifesting the cardinal motor features of Parkinson's disease, which will eventually lead to clinical diagnosis. At this point, neurons are already lost, and addressing dysfunction would not restore ongoing neurodegeneration but could slow the process or even halt it, ideally preserving a pool of functional neurons. Lastly, patients will pass away and the autoptic analysis will provide the definitive diagnosis of the disease based on the neuropathological presentation. Candidate therapeutics to be developed, efficacious in modifying the course of the disease, will have to demonstrate capacity for neuroprotection as well, related to these last stages. Created with BioRender.com.