Parkinson's disease: a dual‐hit hypothesis

By C. Hawkes, K. Del Tredici, H. Braak. Neuropathology and Applied Neurobiology, 2007

928 citations recorded by the source corpus.

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’.

Subfields: Neurology, Sensory Systems

View Paper: https://www.semanticscholar.org/paper/397a3148d49def03c106b53c08c7a385e822f808

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Neurology

Citations in the corpus

Prion-like transmission of protein aggregates in neurodegenerative diseases (2010, background): “Braak and co-workers propose that this spread primarily follows pathways consisting of long unmyelinated axons and that it starts in the olfactory system and gu”
Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders (2010, neutral): “nerve endings [20, 38], either through the olfactory epithelium or GI mucosa.”
Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. (2016, background): “Current hypotheses discuss the gut as the origin of the pathological process that underlies PD [11].”
Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. (2019, background): “It is likely that separate and combinatory processes of initiation via nasal and/or gastric routes and spread contribute to PD and DLB, and in some patients, there may be a dual hit (Hawkes et al., 2007).”
Predicting regional neurodegeneration from the healthy brain functional connectome. (2012, background): “Several mechanisms of transneuronal spread have been proposed, including axonal transport of undetected viruses or toxins (Hawkes et al., 2007; Saper et al., 1987).”
Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease (2011, background): “However, these findings by others, as well as by Braak and colleagues, led to the proposal [14,15] that the ENS may be a route by which a toxin or pathogen initiates the progression of PD over a period of many years.”
Unified Staging System for Lewy Body Disorders: Correlation with Nigrostriatal Degeneration, Cognitive Impairment and Motor Dysfunction (2009, background): “Other authors have offered reasons for this special vulnerability, citing thinly myelinated and lengthy axons [15], an unusually high degree of neuronal plasticity [28, 48] or the spatial proximity to the external environment, with its associated exposure to toxins and infectious agents [14, 43, 58]”