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

Abstract

ABSTRACTBraak and others have proposed that Lewy-type α-synucleinopathy (aSyn) 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. We tested this “body-first” hypothesis by immunohistochemically staining stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects (no brain aSyn), 33 with incidental Lewy body disease (ILBD) (brain aSyn without clinical parkinsonism or dementia) and 53 with PD. Median disease duration for the PD group was 13 years. 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 α-synuclein phosphorylated at serine-129. In the vagus nerve none of the 111 normal subjects had aSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were aSyn-positive. In the stomach none of the 102 normal subjects had aSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were aSyn-positive. As there was no aSyn in the vagus nerve or stomach of subjects without brain aSyn, these results support initiation of aSyn in the brain. The presence of aSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that progression of synucleinopathy to the peripheral nervous system may occur at preclinical stages of Lewy body disease.