The DOI matches its Crossref record; 163 of the 163 references it cites were found in a registry or an index.
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'.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Staging of brain pathology related to sporadic Parkinson’s disease
Braak, H., Tredici, K. D., Rüb, U., de Vos, R. A. I., Jansen Steur, E. N. H., & Braak, E. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00065-9 · Cited by 10,777
Self-citationThe relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease.
Gibb, W. R., & Lees, A. J. (1988) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.51.6.745 · Cited by 3,481
Diagnostic Criteria for Parkinson Disease
Gelb, D. J., Oliver, E., & Gilman, S. (1999) · Archives of Neurology · doi:10.1001/archneur.56.1.33 · Cited by 2,822
Stages in the development of Parkinson’s disease-related pathology
Braak, H., Ghebremedhin, E., Rüb, U., Bratzke, H., & Del Tredici, K. (2004) · Cell and Tissue Research · doi:10.1007/s00441-004-0956-9 · Cited by 2,689
Self-citationHummel, T., Sekinger, B., Wolf, S. R., Pauli, E., & Kobal, G. (1997) · Chemical Senses · doi:10.1093/chemse/22.1.39 · Cited by 2,501
Braak, H., R�b, U., Gai, W. P., & Del Tredici, K. (2003) · Journal of Neural Transmission · doi:10.1007/s00702-002-0808-2 · Cited by 1,683
Self-citationPaxinos, G., & Jürgen, K. (2004) · Cited by 1,478
Braak, H., de Vos, R. A. I., Bohl, J., & Del Tredici, K. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2005.11.012 · Cited by 1,354
Self-citationSchenck, C. H., Bundlie, S. R., & Mahowald, M. W. (1996) · Neurology · doi:10.1212/wnl.46.2.388 · Cited by 1,083
SIC Task Force appraisal of clinical diagnostic criteria for parkinsonian disorders
Litvan, I., Bhatia, K. P., Burn, D. J., Goetz, C. G., Lang, A. E., McKeith, I. G., Quinn, N. P., Sethi, K. D., Shults, C. W., & Wenning, G. K. (2003) · Movement Disorders · doi:10.1002/mds.10459 · Cited by 1,011
Research works printed but not linked: 4
- Braak H, 2005, Parkinson's Disease: Progress in Research., 1
- Sulla M, 1996, Gastric emptying time and gastric motility in patients with untreated Parkinson's disease, Mov Disord, 11, 1041
- Schenck CH, 2003, REM behavior disorder (RBD), delayed emergence of parkinsonism and/or dementia in 65% of older men initially diagnosed with idiopathic RBD, and an analysis of the minimum & maximum tonic and/or phasic electromyographic abnormalities found during REM sleep, Sleep, 26, 316
- 10.1042/bse0410139 · DOI
Cited by
Sorted by citations
Kalia, L. V., & Lang, A. E. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61393-3 · Cited by 6,184
Kim, S., Kwon, S.-H., Kam, T.-I., Panicker, N., Karuppagounder, S. S., Lee, S., Lee, J. H., Kim, W. R., Kook, M., Foss, C. A., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.05.035 · Cited by 1,397
Colonic bacterial composition in Parkinson's disease
Keshavarzian, A., Green, S. J., Engen, P. A., Voigt, R. M., Naqib, A., Forsyth, C. B., Mutlu, E., & Shannon, K. M. (2015) · Movement Disorders · doi:10.1002/mds.26307 · Cited by 1,281
Unger, M. M., Spiegel, J., Dillmann, K.-U., Grundmann, D., Philippeit, H., Bürmann, J., Faßbender, K., Schwiertz, A., & Schäfer, K.-H. (2016) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2016.08.019 · Cited by 1,159
Selective neuronal vulnerability in Parkinson disease
Surmeier, D. J., Obeso, J. A., & Halliday, G. M. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.178 · Cited by 1,116
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
