Proposing Parkinson's Disease to Originate in Either the Brain or the Gut
Parkinson's disease is characterized by the aggregation and spread of misfolded α-synuclein throughout the brain, though, as for all neurodegenerative conditions, there are many layers of cause and effect, and chronic inflammation and cellular dysfunction play noted roles as well. There has been some debate in recent years over whether the α-synuclein aggregation of Parkinson's disease begins in the gut or the brain, with evidence presented for both sides. The authors of this open access paper suggest that both are the case, and Parkinson's can be divided into two subtypes depending on the origin of α-synuclein misfolding.
Parkinson's disease (PD) is a highly heterogeneous disorder, which probably consists of multiple subtypes. Aggregation of misfolded alpha-synuclein and propagation of these proteinacious aggregates through interconnected neural networks is believed to be a crucial pathogenetic factor. It has been hypothesized that the initial pathological alpha-synuclein aggregates originate in the enteric or peripheral nervous system (PNS) and invade the central nervous system (CNS) via retrograde vagal transport. However, evidence from neuropathological studies suggests that not all PD patients can be reconciled with this hypothesis. Importantly, a small fraction of patients do not show pathology in the dorsal motor nucleus of the vagus.
Here, it is hypothesized that PD can be divided into a PNS-first and a CNS-first subtype. The former is tightly associated with REM sleep behavior disorder (RBD) during the prodromal phase and is characterized by marked autonomic damage before involvement of the dopaminergic system. In contrast, the CNS-first phenotype is most often RBD-negative during the prodromal phase and characterized by nigrostriatal dopaminergic dysfunction prior to involvement of the autonomic PNS. The existence of these subtypes is supported by in vivo imaging studies of RBD-positive and RBD-negative patient groups and by histological evidence. The present proposal provides a fresh hypothesis-generating framework for future studies into the etiopathogenesis of PD and seems capable of explaining a number of discrepant findings in the neuropathological literature.
Per is a cool guy - I did an episode with him recently - https://www.youtube.com/watch?v=0vVt8gmz1Ig&t=1s