Objective: To characterize the distribution of alpha-synuclein (aSyn) pathology in multiple tissues and body fluids within the same Parkinson’s disease (PD) subjects and compared to healthy controls (HC).

Background: A major obstacle to development of PD therapeutics is the lack of objective disease measures. aSyn is a lead PD biomarker and multiple reports cite altered levels or forms of aSyn in different biofluids and tissues in PD and prodromal PD. However, there are conflicting reports regarding sensitivity and specificity of peripheral tissue aSyn as a diagnostic biomarker, and within-subject distribution of aSyn in different biofluids and tissues is not well described.

Methods: S4 is a multi-center, cross-sectional, observational study to evaluate aSyn pathology in multiple tissues and biofluids in PD and HC. Biopsies of skin, sigmoid colon, and submandibular gland were obtained. Biofluids collected include cerebrospinal fluid (CSF), saliva, and blood including DNA and RNA. Acquisition of all specimens occurred within a 120 day study window. All specimens were acquired and processed in a standardized manner. Paraffin-embedded tissue sections were stained on an automated Ventana platform with the 5C12 monoclonal antibody. Digital images of the slides were interpreted by neuropathologists blinded to diagnosis. aSyn pathology density on each slide was assessed semi-quantitatively. aSyn was measured in CSF, saliva, and blood compartments using the Biolegend total aSyn assay. Biofluid aSyn analysis accounted for hemoglobin values. Clinical assessments included MDS-UPDRS, MOCA, UPSIT, and dopamine transporter SPECT.

Results: The final sample consists of 60 PD (early, middle and late stage) and 21 HC. aSyn pathology was highly specific for a PD diagnosis in all tissue types; the submandibular gland demonstrated the highest sensitivity. Colonic tissue aSyn had poor sensitivity. In CSF, there were significantly lower levels of total aSyn in HC versus PD groups. Within subjects, preliminary analyses suggest that the measured aSyn biomarkers indicated progression of pathology in step with higher disease stage. Comprehensive analyses are ongoing and will be presented in full.

Conclusions: S4 will contribute to understanding of the distribution of aSyn in biological fluids and peripheral nervous system tissue, providing an assessment of the feasibility and utility of peripheral biomarkers for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/multisite-tissue-and-biofluid-sampling-for-alpha-synuclein-in-parkinsons-disease-the-systemic-synuclein-sampling-study-s4/