Objective: To evaluate the diagnostic accuracy of αSyn-SAAs across established and prodromal non-Parkinsonian synucleinopathies, including Lewy body disorders (DLB), multiple system atrophy (MSA), isolated REM sleep behavior disorder (iRBD), and pure autonomic failure (PAF).

Background: α-Synuclein seed amplification assays (αSyn-SAAs) have emerged as highly sensitive biomarkers for detecting misfolded α-synuclein in Parkinsonian disorders. However, their diagnostic performance across non-Parkinsonian and prodromal synucleinopathies has not been comprehensively synthesized.

Method: A PRISMA-2020–compliant systematic review and diagnostic meta-analysis was performed using PubMed, Embase, and Web of Science through January 2026. Eligible studies were screened after duplicate removal. Study-level 2×2 data were extracted to calculate pooled sensitivity, specificity, likelihood ratios, and diagnostic odds ratios using a bivariate random-effects model. HSROC analysis assessed overall diagnostic performance, with subgroup analyses by biomatrix.

Results: Of 936 identified records, 20 studies were included for qualitative synthesis and 12 studies (>1,200 participants) for meta-analysis. αSyn-SAAs showed high diagnostic accuracy in Lewy body disorders (sensitivity ~95%, specificity ~97%) and prodromal synucleinopathies, including iRBD (≈90%/93%) and PAF (≈92%/99%). Sensitivity was lower in MSA (~63%) despite high specificity (~97%). Forest plots showed consistent performance in Lewy body and prodromal cohorts but greater variability in MSA. HSROC and likelihood-ratio analyses confirmed strong rule-in diagnostic utility, with similar performance across CSF and peripheral tissue biomatrices.

Conclusion: αSyn-SAAs demonstrate robust diagnostic accuracy across multiple non-Parkinsonian synucleinopathies, particularly Lewy body and prodromal disorders. Reduced sensitivity in MSA likely reflects disease-specific α-synuclein strain biology. These findings support the integration of αSyn-SAA into future diagnostic algorithms and biomarker-driven clinical trials in synucleinopathies.

PRISMA 2020 flow diagram for study selection

Forest plot of sensitivity

Forest plot of specificity

Biomatrix-stratified HSROC analysis

Bayesian post-test probability nomogram

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MDS Abstracts - https://www.mdsabstracts.org/abstract/comprehensive-diagnostic-accuracy-of-%ce%b1-synuclein-seed-amplification-assays-across-non-parkinsonian-synucleinopathies-a-systematic-review-and-diagnostic-meta-analysis/