To determine the diagnostic test accuracy (DTA) of alpha-synuclein (α-syn) seed amplification assays (SAAs) in central and peripheral tissues for Parkinson’s disease (PD) diagnosis.

SAAs have emerged as promising tools for detecting misfolded α-syn. Nevertheless, their diagnostic performance varies with assay, sample, and patient population.

PubMed, EMBASE and SCOPUS were searched up to October 2025 for studies evaluating α-syn SAAs in PD. DTA estimates with 95% CIs were pooled using random-effects meta-analysis employing bivariate or, when limited, univariate models. Subgroup analyses were performed by test and sample type.

Twenty-nine studies comprising 4954 samples (3202 idiopathic PD and 1752 controls) were analyzed. About 96% studies employed real-time quaking-induced conversion (RT-QuIC) tests, while 4% used protein misfolding cyclic amplification (PMCA). Most samples (69%) were cerebrospinal fluid (CSF), followed by serum (12%), salivary and nasal gland secretions (10%), oral and intestinal mucosa (6%), and skin (3%).

Overall SAAs pooled sensitivity, specificity and bi-I2 values were 0.88 (0.84-0.92), 0.94 (0.92-0.96) and 0.54, respectively. RT-QuIC showed 0.89 (0.84-0.93) and 0.94 (0.92-0.96), while PMCA showed 0.88 (0.79-0.93) and 0.96 (0.88-0.99). 

CSF showed 0.83 (0.74-0.89), 0.88 (0.79-0.94), and bi-I2 = 0.60; gland secretions 0.71 (0.66-0.76; I2 = 0.49) and 0.93 (0.88-0.96); I2 = 0.26); mucosa 0.63 (0.12-0.95; I2 = 0.9) and 0.92 (0.86-0.96; I2 = 0); serum 0.94 (0.81-0.98; I2 = 0.89) and 0.92 (0.87-0.95; I2 = 0); and skin 0.89 (0.79-0.94; I2 = 0.16) and 0.97 (0.91-0.99); I2 = 0).

The high DTA of α-syn SAAs, particularly in CSF, serum and skin, highlights their potential role to complement PD diagnosis. Nonetheless, studies with larger peripheral sample sizes and lower heterogeneity are necessary to validate our findings.