Parkinson's DiseaseThe Dual Hit Theory Revisited

摘要

Accumulating evidence suggests that sporadic Parkinson's disease (sPD) has a long pro-dromal period during which several nonmotor features develop; in particular, impair-ment of olfaction, vagal dysfunction, and sleep disorder. Early sites of Lewy pathologyare the olfactory bulb and enteric plexuses of the foregut. We propose that a neurotropicpathogen, probably viral, enters the brain via two routes: (a) nasal, with anterogradeprogression into the temporal lobe; and (b) gastric, secondary to swallowing of nasalsecretions in saliva. These secretions might contain a neurotropic pathogen that, afterpenetration of the epithelial lining, could enter axons of the Meissner's plexus and viatranssynaptic transmission reach the preganglionic parasympathetic motor neurons ofthe vagus nerve. This would allow retrograde transport into the medulla and from hereinto the pons and midbrain until the substantia nigra is reached and typical aspectsof disease commence. Evidence for this theory from the perspective of olfactory andautonomic dysfunction is reviewed and the possible routes of pathogenic invasion areconsidered. It is concluded that the most parsimonious explanation for the initial eventsof sPD is pathogenic access to the brain through the foregut and nose—hence the term"dual hit."