Diffusion MRI and α-Synuclein Seed Amplification Status in Parkinson's Disease

Positive α-synuclein seed amplification assay (SAA) is a biomarker found in most people with Parkinson's disease (PD). We explored if free-water (FW) imaging detects microstructural differences in the brains of patients with early PD with SAA+ or SAA- status.

We studied patients with PD with baseline diffusion imaging and α-synuclein SAA data from the Parkinson's Progression Markers Initiative (PPMI). We compared FW, FW corrected fractional anisotropy (FA_T), and clinical characteristics between SAA+ and SAA- groups. We also applied the Automated Imaging Differentiation for Parkinsonism (AIDP) at baseline to classify PD versus atypical parkinsonism, stratified by SAA status.

Among 462 participants (41 SAA- and 421 SAA+), individuals with SAA+ had hyposmia and shorter motor symptom duration before baseline magnetic resonance imaging (MRI). AIDP identified PD in 92.4% (n = 427, 91.6% had SAA+) and classified 7.6% as atypical parkinsonism (n = 35, 85.7% had SAA+). At baseline, SAA+ individuals had lower FW in the superior cerebellar peduncle, compared to SAA- (pFDR < 0.05). No significant differences in FA_T were found between groups.

Positive α-synuclein SAA was associated with focal microstructural differences but did not distinguish broader diffusion MRI (dMRI) changes across FW and FA_T metrics. These findings indicate that molecular confirmation of synuclein aggregation (via SAA) provides limited stratification of neurodegeneration detected by FW imaging in early PD. ANN NEUROL 2026;100:295-304.