Parkinson's disease: a dual-hit hypothesis.
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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’.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'.read more
Citations
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Journal ArticleDOI
Colonic bacterial composition in Parkinson's disease.
Ali Keshavarzian,Stefan J. Green,Phillip A. Engen,Robin M. Voigt,Ankur Naqib,Christopher B. Forsyth,Ece Mutlu,Kathleen M. Shannon +7 more
TL;DR: It is shown that Parkinson's disease (PD) patients have alpha‐synuclein aggregation in their colon with evidence of colonic inflammation, and dysbiosis might be the mechanism of neuroinflammation that leads to α‐Syn misfolding and PD pathology.
Book ChapterDOI
Etiology and Pathogenesis of Parkinson’s Disease
Taku Hatano,Nobutaka Hattori +1 more
TL;DR: Genetic factors clearly contribute to the pathogenesis of Parkinson’s disease, and many studies have shed light on their implication in, not only monogenic, but also sporadic forms of PD.
Journal ArticleDOI
Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls.
Marcus M. Unger,Jörg Spiegel,Klaus-Ulrich Dillmann,David Grundmann,Hannah Philippeit,Jan Bürmann,Klaus Faßbender,Andreas Schwiertz,Karl-Herbert Schäfer +8 more
TL;DR: This study confirms the recently reported association between PD and the abundance of certain gut microbiota and shows a reduction in fecal SCFA concentrations, which might, theoretically, induce alterations in the ENS and contribute to gastrointestinal dysmotility in PD.
Journal ArticleDOI
Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders
Thomas G. Beach,Charles H. Adler,Lucia I. Sue,Linda Vedders,Lih-Fen Lue,Charles L. White,Haru Akiyama,John N. Caviness,Holly A. Shill,Marwan N. Sabbagh,Douglas G. Walker +10 more
TL;DR: Spinal cord and peripheral PASH was most common in subjects with PD and DLB, where it appears likely that it is universally widespread, and within the gastrointestinal tract, there was a rostrocaudal gradient of decreasing PASH frequency and density.
References
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Staging of brain pathology related to sporadic Parkinson’s disease
TL;DR: This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.
Journal ArticleDOI
The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease.
W R Gibb,Andrew J. Lees +1 more
TL;DR: Associated pathological findings suggest that cases of incidental Lewy body disease are presymptomatic cases of Parkinson's disease, and confirm the importance of age (time) in the evolution of the disease.
Journal ArticleDOI
Diagnostic Criteria for Parkinson Disease
TL;DR: A clinical diagnostic classification based on a comprehensive review of the literature regarding the sensitivity and specificity of the characteristic clinical features of PD is proposed: Definite, Probable, and Possible.