ArticleNPJ Parkinson's disease2022
A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson's disease.
Article in NPJ Parkinson's disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers, 1 of them a synthesis that pooled it.
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Who cites it
87 citing papers in PubMed, 1 synthesis or guideline pooled it, 123 citations in OpenAlex.
- Enteric Nervous System Damage by Food Contaminants: A Pathway to Neurodegeneration?Comprehensive reviews in food science and food safety · 2026Pooled it
- Intranasal drug delivery to the brain for neurodegenerative diseases: Current efforts and challenges in delivery platforms and modeling.Advanced drug delivery reviews · 2026Review
- Neuroinflammation and noradrenergic modulation with β2-adrenoceptors: Emerging therapeutic targets for Parkinson's diseases.Neural regeneration research · 2026Article
- Brain-first and body-first subtypes of Lewy body disease.Nature reviews. Neurology · 2026Review
- Environmental hazards and climate change: Unmasking Parkinson's hidden enemies.Journal of Parkinson's disease · 2026Review
- Brain-first versus body-first Parkinson's disease: Differential findings on pupillary, brainstem and vagus sonography.Journal of neurology · 2026Article
- Case report of Parkinson's disease in isolated congenital anosmia with absent olfactory bulbs.NPJ Parkinson's disease · 2026Article
- Perampanel Blocks Transsynaptic α-Synuclein Propagation and Neurodegeneration in a Mouse Model of Lewy Body Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Human and Mouse Alpha-Synuclein Fibrillation: Impact on h-FTAA Binding and Advancing Strain-Specific Biomarkers in PD Animal Models.International journal of molecular sciences · 2026Article
- Peripheral immunochemical considerations in Parkinson disease: sources, targets and crosstalk mechanisms.Journal of translational medicine · 2026Review
- Structure-function coupling in the human brainstem.bioRxiv : the preprint server for biology · 2026Article
- Is motor asymmetry a predictor of non-motor outcomes in Parkinson's disease?Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Spinal cord involvement and cardiovascular autonomic dysfunction in Parkinson's disease.Scientific reports · 2026Article
- REM Sleep Behavior Disorder as a Key Predictor of Cognitive Decline: Insights from a Narrative Review.Sleep science (Sao Paulo, Brazil) · 2026Review
- Single-cell multiomic human brain atlas reveals regulatory drivers of cortical regionality.Nature communications · 2026Article
- Characteristics and mechanisms of cognitive impairment in Parkinson disease.Nature reviews. Neurology · 2026Review
- Multiomic Analysis Reveals Molecular Pathways Associated with Intestinal Aggregation of α-Synuclein.ACS chemical biology · 2026Article
- Olfactory impairment and probable REM sleep behavior disorder in Parkinson's disease: clinical relevance to the single- and dual-hit hypotheses.Frontiers in aging neuroscience · 2026Article
- Micro/Nanoparticles in the Nose-Brain Axis: Implications for Pathogenesis and Therapeutic Interventions.International journal of nanomedicine · 2026Review
- Systematized delusions in a patient with covert hepatic encephalopathy: A clinicopathological insight into prodromal dementia with Lewy bodies.PCN reports : psychiatry and clinical neurosciences · 2025Article
27 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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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