Alpha-synuclein misfolding as a fluid biomarker for Parkinson’s disease and synucleinopathies measured with the iRS platform

Abstract

Misfolding and aggregation of alpha-synuclein (αSyn) plays a key role in the pathophysiology of Parkinson’s disease (PD). It induces cellular and axonal damage already in the early stages of the disease. Despite considerable advances in PD diagnostics by αSyn seed-amplification assays (SAAs), an early and differential diagnosis of PD still represents a major challenge. Here, we extended the immuno-infrared sensor (iRS) platform technology from Alzheimer’s disease (AD), in which β-amyloid misfolding was monitored as a fluid biomarker towards αSyn misfolding in PD. Using the iRS platform technology, we analyzed cerebrospinal fluid (CSF) from two independent cohorts, a discovery and a validation cohort comprising clinically diagnosed PD (n=57), atypical Parkinsonian disorders with αSyn pathology (multiple system atrophy (MSA), n= 5) or Tau pathology (corticobasal degeneration (CBD), n=5, progressive supranuclear palsy (PSP) n=9), and further disease controls (frontotemporal dementia (FTD) n=7 and other, n=51). In the discovery cohort, an AUC of 0.90, 95 %-CL 0.85 – 0.96 is obtained for the differentiation of PD/MSA vs. all controls, and in the validation cohort, an AUC of 0.86, 95 %-CL 0.80 - 0.93, respectively. In the combined dataset, the αSyn misfolding classifies PD/MSA from controls with an AUC of 0.90 (n=134, 95 %-CL 0.85 - 0.96). Using two threshold values instead of one identified people in the continuum between clearly unaffected (low misfolding group) and affected by PD/MSA (high misfolding group) with an intermediate area in between. The controls versus PD/MSA in the low vs. high misfolding group were classified with 97% sensitivity and 92% specificity.