Revisiting the Dual-Hit Hypothesis: Insights from Postmortem Studies in Parkinson's Disease

What is it about?

The dual-hit hypothesis of Parkinson's disease (PD) proposes that an initial neurotropic pathogen leads to αsynuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV), with subsequent invasion of the brain from these entry points. However, the study found that Lewy pathology commonly arises in the enteric nervous system (ENS) without simultaneous involvement of the OB. Cases with mild amygdala-predominant Lewy pathology nearly always showed OB pathology, while those with α-synuclein pathology restricted to the peripheral autonomic nervous system and/or lower brainstem (early body-first LBD cases) rarely had any OB pathology. This suggests a "single-hit OB or autonomic" scenario instead of the original dual-hit hypothesis. Prodromal symptoms like constipation, RBD, and hyposmia do not fully support the dual-hit hypothesis either, as not all patients conform to it. A revised hypothesis might postulate that external trigger factors initiate the first α-synuclein misfolding and aggregation in only one location in most patients, leading to either early amygdala-predominant or early brainstem/PNS-predominant distribution of Lewy pathology. Early amygdalapredominant cases have little or no pathology in the lower brainstem and autonomic/enteric nervous system, while early brainstem/PNS-predominant cases develop autonomic symptoms and RBD years before diagnosis. More studies on neuropathological datasets are needed to reproduce these findings and further investigate the pathogenic mechanisms of PD.

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Why is it important?

This research is important because it challenges the dual-hit hypothesis of Parkinson's disease (PD), which is a widely accepted theory. The study found that the initial Lewy pathology more frequently arises in the enteric nervous system (ENS) rather than the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV), as proposed by the dual-hit hypothesis. Key Takeaways: 1. The study found that Lewy pathology commonly arises in the ENS without concomitant involvement of the OB, supporting a ""single-hit OB or autonomic"" scenario rather than the simultaneous OB and DMV scenario proposed by the original dual-hit hypothesis. 2. The study highlights the need for more studies on neuropathological datasets to reproduce these findings and further validate the revised single-hit hypothesis. 3. The study suggests that the pathologic process may start in either the olfactory bulb or the ENS, but rarely in both simultaneously, which has implications for understanding the etiology of Parkinson's disease and identifying potential risk factors.