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.

Keywords: Parkinson’s disease; alpha-synuclein; autonomic nervous system; connectome; etiology; pathogenesis.

Fig. 1

In the body-first subtype of PD, the initial α-synuclein pathology presumably originates in the enteric or autonomic nervous system and spreads to the CNS via the vagus and sympathetic connectome. A brainstem-predominant profile of Lewy pathology follows. These patients develop RBD in the prodromal phase, have more autonomic symptoms, significant hyposmia, faster motor and non-motor progression, and more rapid cognitive decline. When parkinsonism emerges, it is (on average) more symmetric. In the brain-first subtype of PD, the initial α-synuclein pathology presumably originates in the amygdala or in closely connected structures such as the olfactory bulb. An amygdala-predominant profile of Lewy pathology then develops. These patients are RBD-negative in the prodromal phase, have fewer autonomic symptoms, less frequent hyposmia, slower motor and non-motor progression, and less rapid cognitive decline. When parkinsonism emerges, it is most often asymmetric. Different genetic mutations seem to be associated with one or the other of these phenotypes [18]. Both figures illustrate the site of initial α-synuclein pathology (1) and the subsequent spatial-temporal sequence of progressive Lewy pathology (2–5).

Fig. 2

Overview of the SOC model illustrating how the onset site of pathogenic α-synuclein leads to symmetric vs. asymmetric propagation of α-synuclein pathology. The origin site and symmetry/asymmetry aspects influence the clinical phenotype of patients including the degree of motor and non-motor asymmetry, and the progression rate to dementia. α-syn, α-synuclein; DMV, dorsal motor nucleus of vagus; GI, gastrointestinal; LC, locus coeruleus; SN, substantia nigra; NBM, nucleus basalis of Meynert; NMS, non-motor symptoms.

Fig. 3

A) Schematic representation of important connectome details in PD. Ipsilateral connections outnumber contralateral projections approximately 100-to-1. The commissural projections often show most intense innervation to their contralateral homologs, termed homotypic innervation. The diagram also shows key mono-synaptic connections of the amygdala and brainstem nuclei, which are also predominantly ipsilateral. Importantly, the autonomic innervation of the GI tract from the right and left DMV shows a great deal of overlap. B) Brain-first PD. The originating α-synuclein pathology appears unilaterally, often in the amygdala or closely connected structures such as the olfactory bulb. Due to the predominantly ipsilateral connections in one hemisphere, the pathology spreads initially to ipsilateral structures. At the time of diagnosis (middle column), the ipsilateral degeneration of the substantia nigra gives rise to asymmetric motor symptoms. The asymmetric distribution of α-synuclein persists into later disease stages. C) Body-first PD. The originating α-synuclein pathology, which can arise anywhere in the enteric nervous system, propagates to the DMV bilaterally due to the overlapping vagal innervation. The symmetric α-synuclein pathology then propagates rostrally, and leads to a more symmetric loss of nigrostriatal innervation and more symmetric motor symptoms. When parkinsonism emerges, the global burden of α-synuclein pathology is higher in body-first PD due to the more symmetric involvement of both hemispheres, possibly further promoted by the more marked involvement of ascending, neuromodulatory brainstem nuclei. Measured from the time of parkinsonism onset, the body-first patient is therefore at elevated risk of faster progression and accelerated cognitive decline. Amyg, amygdala; SN, substantia nigra; DMV, dorsal motor nucleus of vagus; ENS, enteric nervous system; PPN, pedunculopontine nuclei.

Fig. 4

A) The DMV nuclei in rats show symmetric deposits of pathological, hyperphosphorylated α-synuclein inclusions following injection of α-synuclein seeds in the duodenum. B) Following unilateral injection of α-synuclein fibrils into the amygdala, α-synuclein inclusions are seen in ipsilateral limbic and cortical structures, with early involvement of the ipsilateral substantia nigra (red insert). No contralateral pathology is seen at this early timepoint. These wild-type rats were both sacrificed three months post-injection. C) Schematic representation of published data from injection of α-synuclein seeds unilaterally into a single CNS location [56, 57, 59]. Markedly asymmetric α-synuclein pathology is evident at the early time point 1. At the later time point 2, progressive accumulation of α-synuclein is seen in nearly all affected regions, but the asymmetry persists. D) The distribution of α-synuclein pathology in the ipsilateral hemisphere at time point 1 is very similar to the α-synuclein distribution in the contralateral hemisphere at time point 2. This suggests that the α-synuclein pathology in the contralateral hemisphere is, in part, promoted by commissural homolog-to-homolog connections from the ipsilateral hemisphere.

Fig. 5

Stylized sketch of the two typical graded profiles of α-synuclein pathology seen in postmortem studies [20–22]. Pathology ranges from none to very severe in 11 anatomical regions sorted according to Braak stages. Cases showing most pathology in the autonomic nuclei and brainstem are hypothesized to be body-first (blue). Cases showing most pathology in the amygdala and entorhinal cortex, but relatively less pathology in the lower brainstem are hypothesized to be brain-first (red). Amyg, amygdala; Cing, cingulate; DMV, dorsal motor nucleus of vagus; Ento, trans-entorhinal cortex; Front, frontal cortex; IML, sympathetic intermediolateral cell column; LC, locus coeruleus; Pariet, parietal cortex; SN, substantia nigra; S-Para, sacral parasympathetic nuclei; Temp, temporal cortex.

Fig. 6

The SOC model predicts that body-first PD shows symmetric α-synuclein pathology, whereas brain-first PD shows asymmetric pathology in the hemispheres. Since only single hemispheres are studied in postmortem studies, this can give rise to the impression that brain-first PD have less Lewy pathology on average. In reality, the most severely affected hemisphere in each brain-first case may show a similar amount of pathology as that seen in both hemispheres of body-first cases.