Simultaneous Brain Iron and α-Synuclein Detection in Patients with Synucleinopathies via Quantitative Susceptibility Mapping MRI

Background α-Synuclein (α-Syn) aggregation and iron deposition drive synucleinopathies, such as Parkinson disease (PD) and multiple system atrophy (MSA), but noninvasive imaging techniques for α-Syn and differentiating between synucleinopathies remain challenging. Purpose To explore whether MRI-based subvoxel quantitative susceptibility mapping (QSM) can help simultaneously measure α-Syn aggregation and iron deposition in patients with synucleinopathies and differentiate between different synucleinopathies. Materials and Methods Phantom and animal (one C3H mouse) experiments were performed to measure the magnetic susceptibility properties of α-Syn. In the prospective study, subvoxel QSM images were acquired from healthy controls (HCs) and participants with PD and MSA who were recruited from October 2021 to September 2024 to assess α-Syn aggregation and iron deposition via diamagnetic and paramagnetic values, respectively. Correlation analysis was performed between subvoxel QSM and symptom scores. Receiver operating characteristic curve analysis was conducted to evaluate subvoxel QSM performance to differentiate participants with synucleinopathies and HCs. Results The diamagnetic property of α-Syn was confirmed. A total of 273 participants (mean age, 59 years ± 8 [SD]; 148 female participants; 62 with MSA, 107 with PD, and 104 with HC) were evaluated. Substantia nigra pars compacta of participants with synucleinopathies showed α-Syn aggregation (mean absolute diamagnetic values: MSA, 0.0109 ppm ± 0.0004; PD, 0.0100 ppm ± 0.0002; HC, 0.0088 ppm ± 0.0003; <i>P</i> < .001) and iron deposition (mean paramagnetic values: MSA, 0.0992 ppm ± 0.0037; PD, 0.0897 ppm ± 0.0018; HC, 0.0762 ppm ± 0.0018; <i>P</i> < .001). The MSA group showed abnormalities in various brain regions, which correlated with symptoms (<i>r</i> > .26; <i>P</i> < .05). Subvoxel QSM enabled synucleinopathy differentiation (areas under receiver operating characteristic curve: PD vs HC, 0.87 [95% CI: 0.82, 0.92]; MSA vs HC, 0.94 [95% CI: 0.90, 0.98]; and PD vs MSA, 0.96 [95% CI: 0.93, 0.98]). Conclusion Subvoxel QSM enabled simultaneous measurement of α-Syn aggregation and iron deposition in patients with synucleinopathies, effectively distinguishing PD from MSA and both from HCs. © The Author(s) 2026. Published by the Radiological Society of North America under a CC BY 4.0 license. <i>Supplemental material is available for this article.</i>