Parkinson's disease: a dual-hit hypothesis

Abstract

Accumulating evidence suggests that sporadic Parkinson's disease has a long prodromal period during which several non-motor features develop, in particular, impairment of olfaction, vagal dysfunction and sleep disorder. Early sites of Lewy pathology are the olfactory bulb and enteric plexus of the stomach. We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (i) nasal, with anterograde progression into the temporal lobe; and (ii) 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 neurones 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 sporadic Parkinson's disease is pathogenic access to the brain through the stomach and nose - hence the term 'dual-hit'.

Figure 1

(A–B, left hand side) to illustrate the mode of spread of herpes simplex virus following injection into peripheral portions of the vagus nerve in the rat medulla oblongata, adapted and reproduced in part with permission from Blessing et al.[154]. (A–B, right hand side) to show the topographical distribution pattern of α‐synuclein pathology in the human medulla in stages 1 and 2 of sporadic Parkinson's disease, adapted and reproduced in part with permission from Del Tredici et al.[21]. amb, ambiguus nucleus; dmo, dorsal motor nucleus of the vagus (marked in green); gig, gigantocellular reticular nucleus, iop, inferior olivary nucleus, principal subnucleus; irz, intermediate reticular zone; rob, nucleus raphes obscurus; sol, solitary tract; XII, motor nucleus of the hypoglossal nerve.

Figure 2

Alpha‐synuclein immunoreactions (Syn‐1: 1:2 000, Transduction Laboratories) in 6‐μm paraffin sections showing Lewy bodies (A, arrows and B) in the Auerbach plexus of the human oesophagus. Scale bar in (B) is valid for (A). Reproduced in part with permission from Braak et al. [24]. Aggregated axonal α‐synuclein inclusions (Lewy neurites) in the gastric Meissner plexus (C,D). Notice how the terminal ramifications of abnormally altered axons extend through the lamina propria of the gastric mucosa and run parallel to the gastric glands (D). Syn‐1 immunoreactions in 150‐μm cryosections. Scale bar in (D) also applies to (C). Adapted and reproduced with permission from Braak et al. [88].

Figure 3

Simplified diagram showing the vagal interconnections between the enteric nervous system and medulla oblongata. A neurotropic agent capable of passing through the mucosal epithelial barrier of the stomach could enter terminal axons of postganglionic VIPergic neurones (black, rounded cell somata) in the submucosal Meissner plexus and, via retrograde axonal and transneuronal transport (black, rounded cell somata in the Auerbach plexus), reach the preganglionic cholinergic neurones (black, diamond‐shaped cell somata) of the dorsal motor nucleus of the vagus in the lower brainstem. Reproduced with permission from Braak et al. [88].

Figure 4

Two schematic drawings. (A) The essentially caudal‐rostral expansion (white arrows) of the Lewy body pathology in the brain after it attains a foothold in the dorsal motor nucleus of the vagus in the medulla oblongata (here, in black). The other consistently involved induction site in sporadic Parkinson's disease is the olfactory bulb (black). Reproduced with permission from Braak et al. [22]. (B) Median view of a mediosagittal section through the human brain: lines A and B indicate the respective planes of the frontal sections through the medulla oblongata depicted in Figure 1. Adapted and reproduced in part with permission from Del Tredici et al. [21].