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Cited by 127Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNeuroinflammation and Neurodegeneration Mechanisms

A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson’s disease

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Borghammer, Per, Just, Mie Kristine, Horsager, Jacob, Skjærbæk, Casper, Raunio, Anna, Kok, Eloise H., Savola, Sara, Murayama, Shigeo +3 more·2022·npj Parkinson's Disease
DOI 10.1038/s41531-022-00436-2PMC PMC9712280
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Abstract

The dual-hit hypothesis of Parkinson’s disease (PD) originally postulated that a neurotropic pathogen leads to formation of α-synuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV) and then invades the brain from these two entry points. Little work has been conducted to validate an important underlying premise for the dual-hit hypothesis, namely that the initial Lewy pathology does arise simultaneously in the OB and the enteric nervous system (ENS) plexuses and DMV at the earliest disease stage. We conducted a focused re-analysis of two postmortem datasets, which included large numbers of mild Lewy body disease (LBD) cases. We found that cases with α-synuclein pathology restricted to the peripheral autonomic nervous system and/or lower brainstem (early body-first LBD cases) very rarely had any OB pathology, suggesting that Lewy pathology commonly arises in the ENS without concomitant involvement of the OB. In contrast, cases with mild amygdala-predominant Lewy pathology (early brain-first LBD cases) nearly always showed OB pathology. This is compatible with the first pathology being triggered in the OB or amygdala followed by secondary spreading to connected structures, but without early involvement of the ENS or lower brainstem. These observations support that the pathologic process starts in either the olfactory bulb or the ENS, but rarely in the olfactory bulb and gut simultaneously. More studies on neuropathological datasets are warranted to reproduce these findings. The agreement between the revised single-hit hypothesis and the recently proposed brain-first vs. body-first model of LBD is discussed.

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  • A recent revision based on post-mortem analysis of many patients with mild Lewy body disease including PD and other related α-synucleinopathies, suggests that α-synuclein pathology typically originates in either the olfactory bulb or the peripheral nervous system (including the DMV), but rarely both simultaneously.

    “However, a recent revision based on post-mortem analysis of many patients with mild Lewy body disease including PD and other related α-synucleinopathies, suggests that α-synuclein pathology typically originates in either the olfactory bulb or the peripheral nervous system (including the DMV), but rarely both simultaneously [53].”

    From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [53]

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References 68 · Cited by 127

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Authors
Borghammer, P., Just, M. K., Horsager, J., Skjærbæk, C., Raunio, A., Kok, E. H., Savola, S., Murayama, S., Saito, Y., Myllykangas, L., & Van Den Berge, N.
Affiliations
  • Aarhus University (DK)
  • Aarhus University Hospital (DK)
  • University of Helsinki (FI)
  • Tokyo Metropolitan Institute of Gerontology (JP)
Corresponding author
Borghammer, Per
ORCID
Venue
npj Parkinson's Disease
Publisher
Springer Science and Business Media LLC
Published
2022-11-30
Volume
8
Issue
1
Pages
166-166
ISSN
2373-8057 (ISSN-L)
DOI
10.1038/s41531-022-00436-2
PMC
PMC9712280
OpenAlex
W4310384354
Cited by
127
References
68
Citations by year
2026: 21 · 2025: 29 · 2024: 43 · 2023: 34
FWCI
13.95
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Parkinson s Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • Scopus (Elsevier) (submittedVersion, cc-by)
  • Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
Funders
  • Japan Agency for Medical Research and Development (JP 21wm0425019)
  • Lundbeckfonden
  • H. Lundbeck A/S
  • Japan Society for the Promotion of Science (22K07538, JP21wm0425019, 22K00570, 22H04923, 341007)
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, Lewy body disease, alpha-synuclein pathology, olfactory bulb, dorsal motor nucleus of the vagus, enteric nervous system, amygdala, neuropathology

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