Duodenal Biopsy May Aid Parkinson’s Disease Diagnosis Duodenal Biopsy May Aid Parkinson’s Disease Diagnosis

The study covered in this summary was published on medRxiv.org as a preprint and has not yet been peer reviewed.

Key Takeaways

  • In all tested patients with Parkinson’s disease (PD), immunohistochemistry analysis of duodenal wall biopsy samples showed there was elevated immunoreactivity for aggregated alpha-Synuclein (αSyn) when compared with controls.

  • Evaluation of enteric glial cells (EGC) showed increased size and density in patients with PD compared with controls, suggesting reactive gliosis.  

Why This Matters

  • The study showed that duodenal biopsy may be a reliable tool for characterizing Parkinson’s disease pathology in the GI tract and help discern patients with PD from the general population.

  • The study recommended diagnostic evaluation parameters for immunohistochemistry involving a combination of a morphometric method (standardized for each laboratory) and detection of a single thread-like αSyn antibody immunoreactivity.

  • This study addressed a knowledge gap for human studies investigating bidirectional pathological protein aggregates in the gut–brain axis in Parkinson’s disease. 

  • The study helped determine which antibody should be used in peripheral tissues to distinguish patients with PD from controls. Also, the study helped to determine the precise mechanism for how EGC contribute to PD pathogenesis.

Study Design

  • Eighteen patients with symptomatic advanced Parkinson’s disease who underwent percutaneous endoscopic gastrostomy and jejunal tube (PEG-J) were compared with 18 age and sex-matched healthy control participants that underwent diagnostic endoscopy, each with four 3-mm duodenal wall biopsy samples taken.

  • Immunohistochemistry was performed to determine the density and size of αSyn-5G4+ aggregates and glial fibrillary acidic protein (GFAP+) aggregates. 

  • Immunoreactive elements involving αSyn-5G4 were detected in duodenal specimens and were classified according to morphological criteria into four immunoreactivity groups (1 – Compact and globular, 2 – granular cellular, 3 – dot-like, 4 – threaded).

Key Results

  • The 18 enrolled patients had advanced PD with a mean duration of 11.3 years and required levodopa/carbidopa intestinal gel (LCIG) infusion.

  • Among the four morphological immunoreactivity groups, threaded immunoreactivities represented the most reliable immunoreactivity type to discern PD from healthy controls. Regardless of morphology, immunoreactivity for aggregated αSyn was absent (4/14) or barely detectable (14/18) in controls, while all duodenal samples (18/18) from patients with PD were characterized by immunoreactivity for aggregated αSyn.

  • Semi-automatic morphometric quantification for the burden of aggregated αSyn immunoreactivity showed significant higher immunoreactive tissue area in patients with PD compared to controls (PD: mean % area, 1.58 %; control group: mean % area, 0.18 %; P < .0001).

  • Immunofluorescent staining confirmed colocalization between αSyn-5G4 threaded immunoreactivities and β-III tubulin, a pan-neuronal and neuritic marker, which indicated that aggregated αSyn deposits localized in duodenal nerve fibers of the mucosa and submucosa.

  • Morphometric analysis of glial cell density showed increased EGC density (PD mean: 95.2 ±32.6; control mean: 45.8 ±14.9; P < .0001) and increased EGC size (PD mean: 28.2 ±1.4 µm2; control mean: 25.1 ±1.2 µm2, P < .0001), suggesting local reactive gliosis.

  • Correlation analysis between αSyn-5G4 immunoreactive area, EGC density and EGC cell size in the duodenum revealed a strong correlation (Rs = 0.751, P < .0001 and Rs = 0.741, P < .0001, respectively).

Limitations

Disclosures

Angelo Antonini, MD, PhD, has received compensation for consultancy and speaker related activities from UCB, Boehringer Ingelheim, Ever Pharma, General Electric, Britannia, AbbVie, Kyowa Kirin, Zambon, Bial, Theravance, Biopharma, Jazz Pharmaceuticals, Roche, Medscape, and receives research support from Bial, Lundbeck, Roche, and Angelini Pharmaceuticals. He serves as consultant for Boehringer Ingelheim for legal cases on pathological gambling.  Gabor Kovacs, MD, PhD, has served as an advisor for Biogen and received royalty for 5G4 synuclein antibody and publishing royalties from Wiley, Cambridge University Press, and Elsevier.

This is a summary of a preprint research study, “Duodenal alpha-Synuclein pathology and enteric gliosis in advanced Parkinson’s Disease patients,” written by researchers at the University of Padova, Center for Neurodegenerative Disease Research, and the Parkinson and Movement Disorders Unit, Center for Rare Neurological Diseases, Padova, Italy on medRxiv, provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.

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