Parkinson's disease: a dual‐hit hypothesis

Hawkes, C. H.; Del Tredici, K.; Braak, H.

doi:10.1111/j.1365-2990.2007.00874.x

Cited by 1,021Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNeuroinflammation and Neurodegeneration Mechanisms

Parkinson's disease: a dual‐hit hypothesis

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

DOI 10.1111/j.1365-2990.2007.00874.xPMC PMC7194308

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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'.

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The double-hit hypothesis proposed by Hawkes et al. supports their theory, pointing out that α-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.
“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]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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When α-synuclein pathology firstly occurred in the olfactory bulbs, it spread further to the brain via the olfactory tract but also went down to the ENS and damaged its neurons.
“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]
Braak and colleagues hypothesized that alpha-synuclein pathology might start in the olfactory bulbs and/or enteric nervous system by an unknown pathogen and/or environmental toxin and then progress to the substantia nigra and further areas of the central nervous system.
“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
The vagal nerve might provide a path for the spread of alpha-synuclein pathology from the enteric nervous system to the brain through the brainstem, midbrain, basal forebrain, and cortical areas.
“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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Duda JE, Lee VMY, Trojanowski JQ. Neuropathology of synuclein aggregates: new insights into mechanism of neurodegenerative diseases. J Neurosci Res 2000; 61: 121-7
Daum RF, Sekinger B, Kobal G, Lang CJ. Olfactory testing with 'sniffin' sticks' for clinical diagnosis of Parkinson's disease. Nervenarzt 2000; 71: 643-50
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Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon RO. Cardiac sympathetic denervation in Par- kinson's disease. Ann Intern Med 2000; 133: 338-47
Halliday G, Del Tredici K, Braak H. Critical appraisal of the Braak staging of brain. pathology related to sporadic Parkinson's disease. J Neural Transm (Suppl) 2006; 70: 99-103

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“…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), whereas the initiation of the pathological process in the OB can more directly affect the brain via the olfactory tract (Hawkes…”
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Parkinson's Disease: The Dual Hit Theory Revisited
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Self-citation

Authors: Hawkes, C. H., Del Tredici, K., & Braak, H.
Affiliations: Queen's Hospital (GB)
Goethe University Frankfurt (DE)
Corresponding author: Hawkes, C. H.
ORCID: Hawkes, C. H.
Braak, 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
DOI: 10.1111/j.1365-2990.2007.00874.x
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
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Neuropathology and Applied Neurobiology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Deutsche Forschungsgemeinschaft
Topics: Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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Parkinson's disease: a dual‐hit hypothesis

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