Main idea: a new model of the PD pathogenesis is proposed that takes into account the origin site of the initiating α-synuclein pathology and the important role played by the highly lateralized connectivity of the human brain. The SOC model may have greater explanatory power than previously proposed models as it is readily compatible with the two main profiles of α-synuclein pathology seen in postmortem studies: brainstem-predominant and limbic-predominant profiles. The SOC model also readily explains why truncal vagotomy would decrease the risk of PD by 40–50%, and the observation that the peripheral autonomic nervous system is almost completely degenerated in RBD-positive prodromal PD, while the substantia nigra remains mostly intact.
A new model of Parkinson’s disease (PD) pathogenesis is proposed. It incorporates two aspects of alpha-synuclein pathobiology that impact the disease course for each patient. In brain-first cases, it is proposed that the first pathology appears unilaterally, often in the amygdala. The asymmetric distribution of pathology leads to asymmetric dopaminergic degeneration and motor asymmetry. The SOC model is supported by a considerable body of existing evidence and may have improved explanatory power. In body-first cases, the pathology ascends via the vagus to both the left and right dorsal motor nuclei of the vagus owing to the overlapping parasympathetic innervation of the gut. This promotes faster disease progression and accelerated cognitive decline.