Parkinson's Disease: The Dual Hit Theory Revisited

Neuroscience Centre, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 08/2009; 1170(1):615-22. DOI: 10.1111/j.1749-6632.2009.04365.x
Source: PubMed


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."

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Available from: Kelly Del Tredici, Mar 11, 2015
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    • "Recently, a so-called " dual hit " hypothesis has been proposed for Parkinson's disease (PD); this theory postulates a simultaneous involvement of the olfactory system and the DMNV, following aerosolic exposure to an unidentified pathogen which spreads to the ENS after swallowing [10]. Intriguingly, the dual hit hypothesis seems to fit well with a more general theory that could include prions. "
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    • "Parkinson's disease (PD) is a progressive neurological disorder characterized by motor behavior dysfunctions such as tremor, muscle rigidity, postural instability and bradykinesia. Although people affected by PD are subjected to a significant preclinical period of 5–6 years (Schapira and Obeso, 2006; Hawkes et al., 2009; Savica et al., 2010), there are numerous non-motor manifestations including autonomic dysfunction, sensory problems, sleep disorders and neuropsychiatric symptoms that precede the onset of motor disabilities by 20 years or more (Poewe, 2006; Reichmann, 2010). In particular, delayed gastric emptying, bloating from small bowel coordination, constipation and defecatory dysfunction are common occurrences in PD and are predicted to predate motor symptoms by at least a decade (Abbott et al., 2001; Savica et al., 2009). "
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    • "Even slight overexpression or slower degradation of the protein could constitute a risk factor for PD (Ibanez et al. 2004). Whereas the etiology of PD is still unknown and is probably the result of a combination of genetic and environmental factors (Di Monte et al. 2002), Braak and colleagues had postulated the hypothesis that a putative, but still unidentified , environmental pathogen entering by olfactory and/or digestive route could induce αS misfolding and aggregation in specific cell types and reach the brain via a consecutive series of projection neurons (Braak et al. 2006; Hawkes et al. 2009). Searches for environmental factors that might Abstract The etiology of most human neurodegenerative disorders is believed to be multifactorial and consists of an interaction between environmental factors and genetic predisposition. "
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