Blood β-Synuclein and Neurofilament Light Chain During the Course of Prion Disease

Background and objectives: For early diagnosis and disease monitoring of neurodegenerative diseases (NDs) reliable blood biomarkers are needed. Elevated levels of neurofilament light chain protein (NfL), an axonal damage marker, have been described across different NDs with highest values in prion diseases and amyotrophic lateral sclerosis (ALS). Synaptic degeneration is a common early feature in most NDs and seems to precede neuronal degeneration in prion disease. However, synaptic markers in blood are still missing. Here we investigated if the brain specific protein beta-synuclein might be a suitable blood biomarker for early diagnosis and evaluation of synaptic integrity in prion disease.

Methods: We analyzed blood beta-synuclein with a newly established digital ELISA and NfL with single molecule array in samples obtained from human subjects and prion and ALS animal models. Furthermore, beta-synuclein was investigated in brain tissue of Creutzfeldt-Jakob disease (CJD) and control cases.

Results: We investigated 308 patients including 129 prion disease cases, 8 presymptomatic PRNP mutation carriers, 60 ALS, 68 other ND and 43 control patients. In CJD symptomatic cases beta-synuclein and NfL were markedly increased compared to all other diagnostic groups (p<0.001). In the large majority of pre-symptomatic PRNP mutation carriers beta-synuclein and NfL levels were within normal range. In prion disease animal models, beta-synuclein and NfL displayed normal levels in the pre-symptomatic phase with a sudden elevation at disease onset and a plateau in the symptomatic phase. In contrast to NfL, beta-synuclein was neither elevated in symptomatic ALS patients nor in an ALS animal model. In the discrimination between prion disease and all other groups beta-synuclein (AUC: 0.97, 95% CI: 0.94-0.99, p<0.001) was superior to NfL (AUC: 0.91, 95% CI: 0.88-0.94, p<0.001). Additionally, brain tissue beta-synuclein showed significantly reduced levels in CJD compared to control patients (p<0.001).

Discussion: Blood beta-synuclein was significantly elevated in CJD patients reflecting ongoing synaptic damage and showed good discriminative characteristics. We therefore propose it as a candidate blood marker for early diagnosis and monitoring of synaptic integrity in prion disease.

Classification of evidence: This study provides Class III evidence that serum beta synuclein concentration accurately distinguishes patients with symptomatic CJD from controls.