Objective: This study aimed to profile regional α‑synuclein (α-syn) seeding activity in postmortem brains from Parkinson’s disease (PD) and multiple system atrophy (MSA) and to explore whether α‑syn seed amplification assay (SAA) kinetics reflect disease‑specific pathophysiology and spatiotemporal progression.

Background: The SAAs have emerged as highly sensitive and specific diagnostic tools for synucleinopathies, capable of detecting misfolded α‑synuclein even in prodromal stages. However, their potential contribution to understanding disease biology, particularly regional brain vulnerability and differences between neuronal and glial synucleinopathies, remains limited.

Method: SAAs were performed using postmortem brain homogenates obtained from PD (n=5), MSA (n=5), and non‑synucleinopathy controls with primary age‑related tauopathy (PART, n=5). Six brain regions were analyzed: entorhinal cortex, parietal cortex, hippocampus, cerebellum, substantia nigra, and Sylvian fissure region. Fluorescence kinetics were monitored for 50 hours, and parameters including lag phase and maximum fluorescence were extracted. In PD cases, SAA parameters were further examined in relation to Lewy body Braak stages.

Results: PD samples showed robust α‑syn amplification across all brain regions compared with PART and MSA. The lag phase was significantly shorter in PD than in controls, with the cerebellum providing the clearest separation. MSA demonstrated detectable but regionally heterogeneous seeding activity, with significant kinetic differences between the entorhinal and parietal cortices. In PD, SAA parameters were associated with pathological severity: Braak stage 5–6 cases showed the strongest seeding activity with the shortest lag phases and highest fluorescence signals compared with stage 3. Regional analyses revealed that the entorhinal cortex showed a strong correlation between seeding kinetics and Braak stage, whereas the substantia nigra demonstrated an early saturation pattern.

Conclusion: Regional α‑syn seeding activity reflects the spatiotemporal progression of synuclein pathology and reveals distinct patterns between neuronal and glial synucleinopathies. Beyond diagnostic applications, SAAs may provide a quantitative biochemical approach for assessing regional disease burden and pathological staging in synucleinopathies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/regional-%ce%b1-synuclein-seeding-activity-in-parkinsons-disease-and-multiple-system-atrophy/