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

Abstract

A new model of Parkinson’s disease (PD) pathogenesis is proposed, the α-Synuclein Origin site and Connectome (SOC) model, incorporating two aspects of α-synuclein pathobiology that impact the disease course for each patient: the anatomical location of the initial α-synuclein inclusion, and α-synuclein propagation dependent on the ipsilateral connections that dominate connectivity of the human brain. In some patients, initial α-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 α-synuclein propagation depends on connection strength, a unilateral focus of pathology will disseminate more to the ipsilateral hemisphere. Thus, α-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 α-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 α-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 α-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.

Cardiac sympathetic burden reflects Parkinson disease burden, regardless of high or low orthostatic blood pressure changes

“…Braak’s schema was disputed because its model failed to explain all the subtypes of PD, especially cardiac denervation in early PD 24 . Recent hypothesis of “body-first” subtype PD incorporates the cardiac pathobiology which may be the answer to the observed differences between normal and abnormal 123 I-MIBG groups in this study 25 , 26 . This further enhances the extracranial biomarker role of cardiac denervation in PD.…”

Passive Immunization in Alpha-Synuclein Preclinical Animal Models

“…In extension to the body-first vs. brain-first hypothesis, it has been recently postulated that the clinical representation and distribution of αsyn pathology in those two PD subtypes could be explained by varying disease onset site, body or brain, as well as the neural connectome [ 15 ]. According to this αsyn Origin site and Connectome (SOC) model, in the brain-first subtype, αsyn pathology arises in a single hemisphere of the brain, leading to asymmetric limbic-predominant pathology in the brain, after which it spreads to the body.…”

“…Moreover, MSA patients presenting with parkinsonism may be misdiagnosed as PD [ 14 ]. These α-synucleinopathies progress at different velocities with different intensities, but may evolve to similar advanced disease stages over time where the entire body is affected [ 15 , 16 ].…”

Alpha-Synuclein and Cognitive Decline in Parkinson Disease

“…Thus, the clinical symptoms of the body-first PD subtype are relatively symmetric and exhibit more autonomic prodromal symptoms before the onset of parkinsonism. A recently proposed PD etiopathogenesis model called the Synuclein Origin and Connectome model (SOC model) posits that αS pathobiology is the core feature of PD pathogenesis [174]. Moreover, the anatomical origin of the initial synuclein inclusion and dominant ipsilateral connectivity of the human brain may explain motor asymmetry, the presence of non-motor symptoms (for example, constipation and REM stage behavior disorder), and the variable rates of cognitive decline seen in different subtypes of PD.…”