Objective: To compare free-water (FW) imaging in individuals with Parkinson’s disease (PD), with positive vs. negative cerebrospinal fluid (CSF) α-synuclein seed amplification assay (SAA) status.

Background: Studies show α-synuclein SAA to be a promising biomarker of underlying synuclein pathology in PD. However, some clinical features may contribute to the heterogeneity of SAA status in PD (e.g., genetic subtype; olfactory function). Whether FW imaging can detect microstructural differences in the brains of people with PD having either SAA+ or SAA- results is unknown.

Method: We identified individuals with manifest PD from the Parkinson’s Progression Markers Initiative (https://www.ppmi-info.org/), with concurrent diffusion imaging and α-synuclein SAA data, matched for age and sex. FW and FW corrected fractional anisotropy (FA_T) were compared cross-sectionally between the SAA+ and SAA- groups using an established template of 60 PD regions of interest¹ at baseline and 2-years.

Results: We identified 60 SAA+ and 52 SAA- PD subjects at baseline, with 38 SAA+ and 35 SAA- subjects at 2-years follow-up. Genetic variants were identified for 8/60 in SAA+ (n=3 LRRK2, n=5 GBA), and 13/52 in SAA- (n=4 PRKN, n=8 LRRK2, n=1 GBA). There were no significant differences in olfaction (UPSIT) between SAA+ and SAA- groups. Except for baseline MoCA (27.7±1.7 in SAA+ vs. 27.0±2.0 in SAA- [p=0.03]), there were no significant differences in age, sex, UPDRS-III, or APOEe4 genotype between SAA+/- cohorts. Cross-sectionally at baseline and 2-years, we found significantly higher FA_T in SAA+ individuals compared to SAA-, in numerous PD-related ROIs (e.g., anterior substantia nigra, pedunculopontine nucleus) and also in widespread white matter tracts across the prefrontal, frontal, temporal, occipital and cerebellar lobes (all p_FDR<0.05).

Conclusion: Using PPMI’s comprehensive clinical and biomarker dataset, we identified people with PD and negative SAA and found age- and sex-matched PD cases with positive SAA.  People with PD and SAA+ consistently exhibited higher FA_T in many regions beyond those implicated in PD. FA_T remained elevated at 2-years follow-up, suggesting persistent white matter microstructural changes associated with SAA positivity. Future studies are needed to evaluate potential longitudinal diffusion MRI changes in PD, stratified by SAA status.

References: 1. Archer DB, Bricker JT, Chu WT, et al. Development and Validation of the Automated Imaging Differentiation in Parkinsonism (AID-P): A Multi-Site Machine Learning Study. Lancet Digit Health. Sep 2019;1(5):e222-e231. doi:10.1016/s2589-7500(19)30105-0

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MDS Abstracts - https://www.mdsabstracts.org/abstract/diffusion-mri-changes-linked-to-%ce%b1-synuclein-seed-amplification-status-in-parkinsons-disease/