Autopsy study using immunohistochemistry and RT‑QuIC on brain and gastrointestinal samples from 178 subjects reports GI‑only alpha‑synuclein pathology is rare while brain‑only pathology is substantially more common, and the count of SAA‑positive GI sites correlates with motor and GI autonomic…

This work refines the gut‑versus‑brain origin debate for synucleinopathy, validates RT‑QuIC SAA in GI tissue as a symptom‑linked biomarker useful for patient stratification, and suggests gut‑directed interventions may be relevant only to a minority—important for prioritizing therapeutic targets and…

Braak and others have proposed that Lewy body pathology (LBP) in Parkinson's disease (PD) may arise not only in the brain but alternatively from an initial site in the gastrointestinal (GI) tract with subsequent passage to the central nervous system CNS through the vagus nerve or other routes. We tested this hypothesis by using both immunohistochemistry (IHC) and RT QuIC a form of alpha synuclein seed amplification assay (SAA) to detect alpha synuclein LBP in samples from selected brain regions and 10 GI tract sites taken from autopsies of 50 PD subjects and 128 elderly subjects without parkinsonism or dementia including 34 with IHC identified CNS incidental Lewy body disease (ILBD) and 94 with no Lewy body IHC pathology detected (NLB). A positive SAA or IHC result was restricted to the GI tract in only 2 subjects while LBP by either SAA or IHC was restricted to the brain in 11 subjects. To fairly compare GI-only with brain-only synucleinopathy, however, we would have to do SAA on brain samples from all ILBD and NLB cases in at least 4 critical brain regions: olfactory bulb, medulla, pons, and amygdala. Further SAA of brain regions is estimated, based on the proportional results to date, to potentially identify 21 additional brain-only LBP subjects, for a total of 32, if it were done on all of the NLB subjects. From this brain-only LBP is estimated to be 16 times more common than GI-only LBP. To assess the clinical impact of SAA-positive GI sites we found that the number of positive sites per subject is significantly correlated with UPDRS motor score and SCOPA-AUT GI related scores including those for salivation, straining, constipation, and bowel movement.