Open questions on the nature of parkinson's disease: From triggers to spreading pathology

Parkinson's disease (PD) is a movement disorder identified more than 200 years ago; today it is defined by specific motor symptoms that together receive the name of parkinsonism. PD diagnosis is reached with the full parkinsonian syndrome, but in recent years, a series of non-motor symptoms have arisen as intrinsic components of PD. These non-motor symptoms are variable, creating a widely heterogenous disease presentation. Some non-motor symptoms appear in late disease stages and are explained as the natural progression of PD pathology into other brain centres, including the frontal cortex. Other symptoms can appear a decade or earlier preceding PD diagnosis, particularly hyposmia (loss of smell) and constipation. These early symptoms and the accompanying protein pathology have stimulated a lively conversation about the origin and nature of PD and other related conditions: some authors propose that PD starts in the olfactory mucosa and the gut due to direct exposure to toxins or pathogens. This pathology then travels by anatomically interconnected networks to the midbrain to cause motor symptoms and the cortex to cause late complications. Other models propose that PD develops in multiple independent foci that do not require pathology spread. We will review these hypotheses in the context of recent developments regarding the spread of amyloids and propose a mixed model where a multifocal origin explains the variable presentation of PD, while cell-to-cell spread explains stereotypical disease progression.