The alpha-Synuclein Origin and Connectome Model (SOC Model) of Parkinson's Disease: Explaining Motor Asymmetry, Non-Motor Phenotypes, and Cognitive Decline

A new model of Parkinson's disease (PD) pathogenesis is proposed, the alpha-Synuclein Origin site and Connectome (SOC) model, incorporating two aspects of alpha-synuclein pathobiology that impact the disease course for each patient: the anatomical location of the initial alpha-synuclein inclusion, and alpha-synuclein propagation dependent on the ipsilateral connections that dominate connectivity of the human brain. In some patients, initial alpha-synuclein pathology occurs within the CNS, leading to a brain-first subtype of PD. In others, pathology begins in the peripheral autonomic nervous system, leading to a body-first subtype. In brain-first cases, it is proposed that the first pathology appears unilaterally, often in the amygdala. If alpha-synuclein propagation depends on connection strength, a unilateral focus of pathology will disseminate more to the ipsilateral hemisphere. Thus, alpha-synuclein spreads mainly to ipsilateral structures including the substantia nigra. The asymmetric distribution of pathology leads to asymmetric dopaminergic degeneration and motor asymmetry. In body-first cases, the alpha-synuclein 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. Consequently, the initial alpha-synuclein pathology inside the CNS is more symmetric, which promotes more symmetric propagation in the brainstem, leading to more symmetric dopaminergic degeneration and less motor asymmetry. At diagnosis, body-first patients already have a larger, more symmetric burden of alpha-synuclein pathology, which in turn promotes faster disease progression and accelerated cognitive decline. The SOC model is supported by a considerable body of existing evidence and may have improved explanatory power.

Automated summary

The new model of Parkinson's disease pathogenesis, the SOC model, distinguishes between brain-first and body-first subtypes based on the location of initial alpha-synuclein pathology. Brain-first cases show unilateral pathology, leading to asymmetric dopaminergic degeneration and motor asymmetry, while body-first cases display more symmetric pathology and less motor asymmetry.