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Parkinson's disease: a dual‐hit hypothesis
Open accessAbstract
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'.
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In the citing paper
“The double-hit hypothesis proposed by Hawkes et al.135 supports their theory, pointing out that a-synuclein pathology is transmitted to the midbrain through two different routes, namely, from the nasal cavity to the temporal lobe or from the stomach, followed by nasal secretions in swallowed saliva.135”
From The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options (2021) · cites this paper as [135]
Experimental — accuracy not yet measuredIn the citing paper
“Conversely, when the α-synuclein pathology firstly occurred in the olfactory bulbs, it spread further to the brain via the olfactory tract but it also went down to the ENS and it damaged its neurons [402].”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [402]
In the citing paper
“Braak and colleagues hypothesized that alpha-synuclein pathology might start in either the OB and/or in the ENS possibly by an unknown pathogen and/or environmental toxin and then progresses towards the SN and further areas in the CNS.”
From The Gut-Brain Axis in Parkinson’s Disease: Possibilities for Food-Based Therapies (2017) · cites this paper as Hawkes et al., 2007
In the citing paper
“The vagal nerve might provide a path for the spread of alpha-synuclein pathology from the ENS to the brain through the brainstem, midbrain, basal forebrain and finally the cortical areas (Braak et al., 2003;Hawkes et al., 2007)”
From The Gut-Brain Axis in Parkinson’s Disease: Possibilities for Food-Based Therapies (2017) · cites this paper as Hawkes et al., 2007
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“For example, neurotoxicants or viruses may enter the body via the nasal cavity or the digestive tract (Hawkes et al. 2007, 2009), and, in susceptible individuals, may initiate Lewy pathology in the olfactory bulb or the enteric nerves (Doty 2008; Hawkes et al. 2007, 2009; Reichmann 2011); over…”
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Metadata
- Authors
- Hawkes, C. H., Del Tredici, K., & Braak, H.
- Affiliations
- Queen's Hospital (GB)
- Goethe University Frankfurt (DE)
- Corresponding author
- Hawkes, C. H.
- Venue
- Neuropathology and Applied Neurobiology
- Publisher
- Wiley
- Published
- 2007-10-24
- Volume
- 33
- Issue
- 6
- Pages
- 599-614
- ISSN
- 0305-1846 (ISSN-L)
- 1365-2990
- PMC
- PMC7194308
- OpenAlex
- W2105047187
- Cited by
- 1,021
- References
- 163
- Citations by year
- 2026: 35 · 2025: 59 · 2024: 87 · 2023: 82 · 2022: 104 · 2021: 117 · 2020: 83 · 2019: 59 · 2018: 49 · 2017: 63 · 2016: 41 · 2015: 33 · 2014: 32 · 2013: 40 · 2012: 33
- FWCI
- 2.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuropathology and Applied Neurobiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Parkinson's disease, neurotropic viruses, olfactory dysfunction, Lewy bodies, vagal dysfunction, sleep disorder, olfactory bulb, submucosal plexus, vagus nerve, substantia nigra, prodromal Parkinson's disease, viral pathogenesis
- MeSH terms
- Animals, Olfaction Disorders, Gastrointestinal Diseases, Heart Diseases, Humans, Models, Neurological, Parkinson Disease, Sleep Wake Disorders, Virus Diseases
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