Objective: The aim of this study was to evaluate colonic mucosa staining using the 5G4 antibody, specific only for the disease-associated form of α-synuclein, in a deeply phenotyped cohort of clinically manifest PD patients, patients meeting MDS research criteria for prodromal PD (pPD), and healthy controls (HC) not meeting the prodromal PD criteria.

Background: Previous studies point to a potential role of peripheral tissue biopsies as potential biomarkers of PD including its prodromal stages. Recently, a monoclonal α-synuclein antibody (clone 5G4) has been reported to show high reactivity for disease-associated forms, including oligomers, of α-synuclein, with superior results in comparative immunohistochemical studies in the CNS.1

Methods: Patients undergoing diagnostic colonoscopies were screened for all risk and prodromal markers from the MDS research criteria for prodromal PD, except genetic testing and PET/SPECT studies. Immunoreactivity for 5G4 antibody was performed in formalin-fixed in vivo biopsy samples of the colonic mucosa of patients with manifest PD (n=6), pPD (n=7) and HCs (n=17) and were evaluated by two experienced independent and blinded raters.

Results: Pathological 5G4 positive neuritic structures were present in 5/6 clinically manifest PD patients, 4/7 pPD subjects and 2/17 HCs, yielding sensitivity 83.3%, specificity 88.2%, positive predictive value 71.43% and negative predictive value 93.75% for distinguishing manifest PD from healthy controls; and sensitivity 57.1%, specificity 88.2%, positive predictive value 66.7% and negative predictive value 83.3% for distinguishing probable pPD subjects from HCs. Both HCs with positive 5G4 immunostaining reported previous frequent pesticide exposure, while one of them had also constipation, hyposmia and increased MDS-UPDRS part III score, however, she did not exceed the threshold for probable prodromal PD.

Conclusions: 5G4 immunoreactivity in colonic mucosa is able to distinguish clinically manifest and prodromal PD patients from healthy controls. Although these results need to be confirmed in independent and larger cohorts, our study suggests a predictive value of diagnostic colon biopsies containing mucosal tissue with nerve structures.

References: 1. Kovacs GG, Wagner U, Dumont B, et al. An antibody with high reactivity for disease-associated α-synuclein, reveals extensive brain pathology. Acta Neuropathol 2012; 124: 37-50.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/%ce%b1-synuclein-antibody-5g4-identifies-manifest-and-prodromal-parkinsons-disease-in-colonic-mucosa/