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. 2021;11(4):1833-1843.
doi: 10.3233/JPD-212733.

Vagus Nerve and Stomach Synucleinopathy in Parkinson's Disease, Incidental Lewy Body Disease, and Normal Elderly Subjects: Evidence Against the "Body-First" Hypothesis

Thomas G Beach  1 , Charles H Adler  2 , Lucia I Sue  1 , Holly A Shill  3 , Erika Driver-Dunckley  2 , Shyamal H Mehta  2 , Anthony J Intorcia  1 , Michael J Glass  1 , Jessica E Walker  1 , Richard Arce  1 , Courtney M Nelson  1 , Geidy E Serrano  1
Affiliations

Vagus Nerve and Stomach Synucleinopathy in Parkinson's Disease, Incidental Lewy Body Disease, and Normal Elderly Subjects: Evidence Against the "Body-First" Hypothesis

Thomas G Beach et al. J Parkinsons Dis. 2021.

Abstract

Background: Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson's disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla.

Objective: We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD.

Methods: Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were taken from the gastric body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology.

Results: Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive.

Conclusion: As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease.

Keywords: Pathology; autopsy; etiology; gastrointestinal; pathogenesis; peripheral nerve.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare the following potential conflicts of interest:

TGB: Consultant, scientific advisory board and stock options with Vivid Genomics; Honorarium for invited lecture from Roche Diagnostics.

CHA: Consultant, Amneal Pharmaceuticals; Eisai Pharmaceuticals; Jazz Pharmaceuticals; Neurocrine,Biosciences; Cionic Inc.

LIS: None

HAS: Advisory board, Acorda Therapeutics; Jazz Pharmaceuticals.

ED-D: Clinical trials, AbbVie Inc; Biogen Inc; UCB Pharma

SHM: Consultant, CNS Ratings; Adamas Pharmaceuticals; Abbott Laboratories

AJI: None

MJG: None

JEW: None

RA: None

CMN: None

GES: None

Figures

Figure 1.
Figure 1.
Photomicrographs of vagus nerve and stomach from four different PD subjects, immunohistochemically stained for phosphorylated α-synuclein (black) and counterstained with Neutral Red (red). A and B are longitudinal sections of vagus nerve at low (A) and medium (B) magnification. C and D show short fibers and puncta in the stomach mucosa. E shows short fibers applied to the peripheral surface on an arteriole in the submucosa. F shows puncta within an intermyenteric ganglion. Calibration bar in F represents 100 μm for C-F, 400 μm for B and 800 μm for A.
See this image and copyright information in PMC

References

    1. Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Akiyama H, Caviness JN, Shill HA, Sabbagh MN, Walker DG (2010) Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119, 689–702. - PMC - PubMed
    1. Adler CH , Beach TG (2016) Neuropathological basis of nonmotor manifestations of Parkinson's disease. Mov Disord 31, 1114–1119. - PMC - PubMed
    1. Adler CH, Beach TG, Zhang N, Shill HA, Driver-Dunckley E, Caviness JN, Mehta SH, Sabbagh MN, Serrano GE, Sue LI, Belden CM, Powell J, Jacobson SA, Zamrini E, Shprecher D, Davis KJ, Dugger BN, Hentz JG (2019) Unified Staging System for Lewy Body Disorders: Clinicopathologic Correlations and Comparison to Braak Staging. J Neuropathol Exp Neurol 78, 891–899. - PMC - PubMed
    1. Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J, Sasse J, Boyer S, Shirohi S, Brooks R, Eschbacher J, Akiyama H, Caviness J, Shill HA, Connor DJ, Sabbagh MN, Walker DG (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117, 613–634. - PMC - PubMed
    1. Serrano GE, Shprecher D, Callan M, Cutler B, Glass M, Zhang N, Walker J, Intorcia A, Adler CH, Shill HA, Driver-Dunckley E, Mehta SH, Belden CM, Zamrini E, Sue LI, Vargas D, Beach TG (2020) Cardiac sympathetic denervation and synucleinopathy in Alzheimer's disease with brain Lewy body disease. Brain Commun 2 (in press). - PMC - PubMed

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