Parkinson's disease: the dual hit theory revisited.

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