The absence of orthostatic heart rate increase is associated with cognitive impairment in Parkinson’s disease

Tanaka, Ryota; Yamashiro, Kazuo; Ogawa, Takashi; Oyama, Genko; Nishioka, Kenya; Umemura, Atsushi; Shimo, Yasushi

doi:10.1371/journal.pone.0240491

Cited by 10 publications

(5 citation statements)

References 32 publications

(37 reference statements)

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“…Furthermore, bilateral PNS-to-CNS invasion of pathology, due to overlapping bilateral vagal and sympathetic innervation of the gastro-intestinal (GI) tract, causes a more bilateral disease progression in the brain of these patients. This wider disseminated pathology, including more bilateral involvement of cerebral structures, could explain the well-documented faster symptomatic progression and accelerated dementia in clinical body-first Lewy body disease [27][28][29][30][31][32][33][34] . Note that the majority of patients with Dementia with Lewy bodies are probably bodyfirst, whereas only approximately 1/3 of PD patients show the body-first clinical phenotype 23,[35][36][37] .…”

Section: Discussionmentioning

confidence: 98%

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

Borghammer

Just

Horsager

et al. 2022

npj Parkinsons Dis.

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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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Section: Discussionmentioning

confidence: 98%

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

Borghammer

Just

Horsager

et al. 2022

npj Parkinsons Dis.

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“…However, even if HR values collected during the orthostatic position were higher in the COVID + group than controls, HR did not significantly increase in the COVID + group despite an evident drop in systolic and/or diastolic blood pressure. This finding could suggest a neurogenic nature of SARS-CoV-2-related OH [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Autonomic dysfunction in non-critically ill COVID-19 patients during the acute phase of disease: an observational, cross-sectional study

et al. 2022

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Introduction Evidence is emerging about an extra-pulmonary involvement of SARS-CoV-2, including the nervous system. Autonomic dysfunction in patients recovering from acute coronavirus disease 2019 (COVID-19) has been recently described. Dysautonomic symptoms have been reported in the acute phase of the disease, but clear evidence is lacking, especially in the non-critical forms of the infection. Objective The aim of this study is to assess the prevalence of dysautonomia in acute, non-critically ill COVID-19 patients. Methods In this observational, cross-sectional study, we compared 38 non-critically ill patients with acute COVID-19 (COVID + group) to 38 healthy volunteers (COVID − group) in order to assess the prevalence of signs and symptoms of dysautonomia through the administration of the composite autonomic symptom score 31 (COMPASS-31) and an active standing test. Comparisons between groups were performed by means of both univariate and multivariate analyses. Results The prevalence of orthostatic hypotension was significantly higher in the COVID + group. Higher total scores of COMPASS-31 were observed in the COVID + group than controls. Significant differences between groups emerged in the secretomotor, orthostatic intolerance, and gastrointestinal COMPASS-31 domains. All these results maintained the statistical significance after the adjustment for concomitant drugs with a known effect on the autonomic nervous system assumed by the study participants, except for the differences in the gastrointestinal domain of COMPASS-31. Conclusion Our results suggest that an autonomic dysfunction could be an early manifestation of COVID-19, even in the contest of mild forms of the infection.

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“…However, a large body of evidence disagrees with this. On the contrary, it is well established that increased risk of cognitive decline and dementia clusters with RBD, constipation, and orthostatic hypotension-all markers of the body-first subtype [70,[101][102][103]. Longitudinally, constipation and RBD predicts faster cognitive decline [104].…”

Section: The Soc Model Predicts Differences In Cognitive Declinementioning

confidence: 99%

The α-Synuclein Origin and Connectome Model (SOC Model) of Parkinson’s Disease: Explaining Motor Asymmetry, Non-Motor Phenotypes, and Cognitive Decline

Borghammer

2021

JPD

132

111

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A new model of Parkinson’s disease (PD) pathogenesis is proposed, the α-Synuclein Origin site and Connectome (SOC) model, incorporating two aspects of α-synuclein pathobiology that impact the disease course for each patient: the anatomical location of the initial α-synuclein inclusion, and α-synuclein propagation dependent on the ipsilateral connections that dominate connectivity of the human brain. In some patients, initial α-synuclein pathology occurs within the CNS, leading to a brain-first subtype of PD. In others, pathology begins in the peripheral autonomic nervous system, leading to a body-first subtype. In brain-first cases, it is proposed that the first pathology appears unilaterally, often in the amygdala. If α-synuclein propagation depends on connection strength, a unilateral focus of pathology will disseminate more to the ipsilateral hemisphere. Thus, α-synuclein spreads mainly to ipsilateral structures including the substantia nigra. The asymmetric distribution of pathology leads to asymmetric dopaminergic degeneration and motor asymmetry. In body-first cases, the α-synuclein pathology ascends via the vagus to both the left and right dorsal motor nuclei of the vagus owing to the overlapping parasympathetic innervation of the gut. Consequently, the initial α-synuclein pathology inside the CNS is more symmetric, which promotes more symmetric propagation in the brainstem, leading to more symmetric dopaminergic degeneration and less motor asymmetry. At diagnosis, body-first patients already have a larger, more symmetric burden of α-synuclein pathology, which in turn promotes faster disease progression and accelerated cognitive decline. The SOC model is supported by a considerable body of existing evidence and may have improved explanatory power.

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The absence of orthostatic heart rate increase is associated with cognitive impairment in Parkinson’s disease

Cited by 10 publications

References 32 publications

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

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

Autonomic dysfunction in non-critically ill COVID-19 patients during the acute phase of disease: an observational, cross-sectional study

The α-Synuclein Origin and Connectome Model (SOC Model) of Parkinson’s Disease: Explaining Motor Asymmetry, Non-Motor Phenotypes, and Cognitive Decline

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