Brain-Only Versus GI-Only Synucleinopathy: A Comprehensive Autopsy Study With Both IHC and SAA

Area of Science:

• Neuropathology
• Gastroenterology
• Neurodegenerative Diseases

Background:

• Braak's hypothesis suggests Lewy body pathology (LBP) in Parkinson's disease (PD) may originate in the gastrointestinal (GI) tract and spread to the central nervous system (CNS).
• Investigating the origin and prevalence of LBP is crucial for understanding PD pathogenesis.

Purpose of the Study:

• To test Braak's hypothesis by comparing the prevalence of alpha-synuclein LBP in the GI tract versus the brain in Parkinson's disease (PD) and control subjects.
• To assess the clinical correlation of GI tract LBP with PD symptoms.

Main Methods:

• Utilized immunohistochemistry (IHC) and RT QuIC (alpha-synuclein seed amplification assay - SAA) to detect LBP.
• Analyzed autopsy samples from 50 PD subjects and 128 elderly controls (including incidental LBP and no LBP groups).
• Examined 10 GI tract sites and selected brain regions.

Main Results:

• LBP restricted to the GI tract was rare (2 subjects), while brain-restricted LBP was more common (11 subjects, estimated 32 with further testing).
• Brain-only LBP is estimated to be 16 times more prevalent than GI-only LBP.
• The number of SAA-positive GI sites correlated significantly with UPDRS motor scores and GI-related autonomic dysfunction (e.g., constipation, bowel movement issues).

Conclusions:

• The study provides evidence that while GI tract LBP can occur, brain LBP is significantly more common in PD.
• GI tract LBP is associated with clinical disease severity, supporting a potential role in PD progression.
• Further research on brain regions is needed to fully characterize LBP distribution.