Objective: To evaluate whether integrating dermal α-synuclein and 4R-tau seed amplification assays (SAAs) with serum neurofilament light chain (NfL) improves diagnostic precision in neurodegenerative parkinsonian syndromes beyond single-biomarker strategies.

Background: α-Synuclein SAA has transformed biological diagnosis in Parkinson’s disease (PD), but its utility in atypical parkinsonism is limited by reduced specificity due to co-pathology and inability to distinguish PD from multiple system atrophy (MSA) outside of CSF-based approaches requiring lumbar puncture. Relying on α-synuclein SAA alone is insufficient for differential diagnosis of parkinsonian syndromes. A multimodal approach integrating protein-specific seeding assays with markers of neuroaxonal injury may better capture the biological complexity of these disorders.

Method: In a prospective cohort of 229 participants (PD=75, MSA=38, PSP=94, HC=22), dermal α-synuclein and 4R-tau SAAs were performed on a single cervical skin biopsy and serum NfL quantified by Simoa. A discovery cohort (n=166, Toronto) and an independent multi-site validation cohort (n=63, Toronto and Kassel, Germany) were analysed. Integrated logistic regression models were evaluated by 5-fold stratified cross-validation and applied externally without refitting.

Results: α-Synuclein SAA showed high sensitivity for synucleinopathies but was positive in 23% of PSP cases, consistent with co-pathology and associated with faster clinical progression. 4R-tau SAA identified PSP with 88% sensitivity and 94% specificity. Serum NfL robustly distinguished MSA from PD (AUC 0.97) but was independently influenced by white matter hyperintensity burden, underscoring the need for multimodal interpretation. The integrated model significantly outperformed all single markers: ΔAUC +0.285 for PD (p=2.0×10⁻¹⁵), +0.133 for MSA (p=1.1×10⁻⁷), and +0.096 for PSP (p=0.027), with final AUCs of 0.961, 0.904, and 0.970 respectively, reproduced in the independent validation cohort (AUCs 0.953, 0.849, 0.979) without refitting.

Conclusion: Moving beyond single α-synuclein SAA toward a multimodal minimally invasive platform enables biologically informed differential diagnosis of parkinsonian syndromes. Reproducible across two independent international centres, this scalable approach represents a promising step toward integration into clinical practice and trial enrichment strategies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/beyond-%ce%b1-synuclein-saa-a-multimodal-minimally-invasive-platform-for-biologically-informed-diagnosis-of-parkinsonian-syndromes/