Diagnostic Utility of Cerebrospinal Fluid alpha-Synuclein in Creutzfeldt-Jakob Disease: A Systematic Review and Meta-Analysis

Background: Creutzfeldt-Jakob disease (CJD) can be difficult to distinguish clinically from some non-prion neurological diseases. Previous studies have reported markedly increased levels of alpha-synuclein in cerebrospinal fluid (CSF) of CJD patients, indicating that it is a potential diagnostic biomarker. Objective: The aim of this study was to assess the diagnostic power of CSF alpha-synuclein in discriminating CJD from non-prion disorders. Methods: The Ovid MEDLINE, Cochrane, and Embase databases were searched for articles published on or before February 25, 2022, using the search term (prion diseases OR Creutzfeldt-Jakob syndrome) AND (synuclein OR alpha-synuclein). The difference in CSF alpha-synuclein levels between CJD and non-prion diseases was calculated using random-effects models (I-2 > 50%) or fixed-effects models (I-2 <50%) in terms of standardized mean difference (SMD) and 95% confidence interval (CI). The publication bias was estimated using funnel plots and the Egger's test. Results: Ten studies were included in this study. The concentrations of CSF alpha-synuclein were significantly higher in CJD patients compared to total non-prion controls (SMD = 1.98, 95%CI 1.60 to 2.36, p < 0.00001), tauopathies (SMD = 1.34, 95% CI 0.99 to 1.68,p < 0.00001), synucleinopathies (SMD = 1.78, 95% CI 1.11 to 2.44,p < 0.00001), or Alzheimer's (SMD = 1.14, 95%CI 0.95 to 1.33, p < 0.00001). CSF alpha-synuclein could distinguish CJD from non-prion diseases with overall sensitivity of 89% (95% CI 80-95%), specificity of 92% (95% CI 86-95%), and AUC of 0.96 (95% CI: 0.94-0.97). Conclusion: CSF alpha-synuclein has excellent diagnostic value in discriminating CJD from non-prion neurological diseases. Given the high heterogeneity among the included studies, further studies are needed to confirm its clinical utility.