Motor and non-motor circuit disturbances in early Parkinson disease: which happens first?

For the last two decades, pathogenic concepts in Parkinson disease (PD) have revolved around the toxicity and spread of alpha-synuclein. Thus, alpha-synuclein would follow caudo-rostral propagation from the periphery to the central nervous system, first producing non-motor manifestations (such as constipation, sleep disorders and hyposmia), and subsequently impinging upon the mesencephalon to account for the cardinal motor features before reaching the neocortex as the disease evolves towards dementia. This model is the prevailing theory of the principal neurobiological mechanism of disease. Here, we scrutinize the temporal evolution of motor and non-motor manifestations in PD and suggest that, even though the postulated bottom-up mechanisms are likely to be involved, early involvement of the nigrostriatal system is a key and prominent pathophysiological mechanism. Upcoming studies of detailed clinical manifestations with newer neuroimaging techniques will allow us to more closely define, in vivo, the role of alpha-synuclein aggregates with respect to neuronal loss during the onset and progression of PD. A prevailing theory of Parkinson disease pathogenesis revolves around the spread of alpha-synuclein toxicity from the periphery to the brain. In this Review, Blesa and colleagues discuss the idea that, although these bottom-up mechanisms are involved, early neuronal loss in the nigrostriatal system also plays a prominent role.