Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85+

Raunio, Anna; Kaivola, Karri; Tuimala, Jarno; Kero, Mia; Oinas, Minna; Polvikoski, Tuomo; Paetau, Anders; Tienari, Pentti J.; Myllykangas, Liisa

doi:10.1007/s00401-019-02071-3

Cited by 59 publications

(82 citation statements)

References 47 publications

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“…It was high in diffuse neocortical LBD (44/49, 89.7%) and low in amygdala-predominant LBD (1/29, 3.4%). The amygdala variant is thought to be secondary to AD [ 67 , 69 ], and we use the term “olfactory-amygdala” because this type usually involves olfaction. AD with LB exhibits rare α-synuclein deposition in the ENS [ 4 , 31 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases

et al. 2020

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Lewy body disease (LBD) is a spectrum of progressive neurodegenerative disorders characterized by the wide distribution of Lewy bodies and neurites in the central and peripheral nervous system (CNS, PNS). Clinical diagnoses include Parkinson’s disease (PD), dementia with Lewy bodies, or pure autonomic failure. All types of LBD are accompanied by non-motor symptoms (NMSs) including gastrointestinal dysfunctions such as constipation. Its relationship to Lewy body-related α-synucleinopathy (Lewy pathology) of the enteric nervous system (ENS) is attracting attention because it can precede the motor symptoms. To clarify the role of ENS Lewy pathology in disease progression, we performed a clinicopathological study using the Brain Bank for Aging Research in Japan. Five-hundred and eighteen cases were enrolled in the study. Lewy pathology of the CNS and PNS, including the lower esophagus as a representative of the ENS, was examined via autopsy findings. Results showed that one-third of older people (178 cases, 34%) exhibited Lewy pathology, of which 78 cases (43.8%) exhibited the pathology in the esophagus. In the esophageal wall, Auerbach’s plexus (41.6%) was most susceptible to the pathology, followed by the adventitia (33.1%) and Meissner’s plexus (14.6%). Lewy pathology of the esophagus was significantly associated with autonomic failures such as constipation (p < 0.0001) and among PNS regions, correlated the most with LBD progression (r = 0.95, p < 0.05). These findings suggest that the propagation of esophageal Lewy pathology is a predictive factor of LBD.

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Section: Discussionmentioning

confidence: 99%

Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases

et al. 2020

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“…The SOC model assumes that the quantity of ␣synuclein inclusions in a given nucleus or cortical region increases over time [20][21][22]. This gives rise to the phenomenon of gradients: the initially affected neurons tend to show the most severe pathology, and the most recently affected neurons have the lowest density of ␣-synuclein pathology.…”

Section: Overview Of the Soc Modelmentioning

confidence: 99%

“…We previously hypothesized that brain-first PD is equivalent to those postmortem cases with a limbic (amygdala) predominant profile of ␣-synuclein pathology, and that body-first PD is equivalent to a brainstem-predominant distribution of ␣-synuclein pathology [18,19,21,60,61]. The SOC model predicts that those postmortem cases with a brainstempredominant profile will tend to have more symmetric ␣-synuclein pathology compared with the more asymmetric pathology seen in limbic-predominant cases.…”

Section: The Human Connectome and The Soc Modelmentioning

confidence: 99%

“…Importantly, neuropathology studies have documented that the distribution of Lewy pathology shows two general profiles: (1) a brainstem-predominant pattern with the most intense pathology in the lower brainstem, even when the limbic system and cortex are involved; and (2) a limbic-predominant pattern with the most intense pathology in the amygdala and entorhinal cortex, even when the brainstem and cortex are involved (Fig. 5) [21,22,61]. Furthermore, nearly all postmortem human data is compatible with the interpretation that ␣-synuclein pathology in an affected structure accumulates over time.…”

Section: Utility Of the Soc Modelmentioning

confidence: 99%

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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

142

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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“…3 • Postmortem studies have reported two overarching types of Lewy pathology: a brain stem-predominant type with more pathology in the brain stem than more rostral structures and a limbic/amygdala-predominant type, with more pathology near the "center of the brain" compared with more caudal structures. 6 The authors also point to the lack of "gut-only" cases reported in the Arizona autopsies. This group screens the entire digestive tract with 10-15 tissue sections.…”

mentioning

confidence: 98%

The Logic and Pitfalls of Parkinson's as Brain‐ Versus Body‐First Subtypes

Borghammer

Horsager

2021

Movement Disorders

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Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85+

Cited by 59 publications

References 47 publications

Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases

Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases

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

The Logic and Pitfalls of Parkinson's as Brain‐ Versus Body‐First Subtypes

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