Potential separation of multiple system atrophy and Parkinson's disease by susceptibility-derived components

Background: Substantial evidence emphasizes the dysregulation of iron homeostasis, demyelination and oxidative stress in the neurodegenerative process of multiple system atrophy (MSA) and Parkinson's disease (PD), although its clinical implications remain unclear. Recent MRI post-processing techniques leveraging magnetic susceptibility properties provide a noninvasive means to characterize iron, myelin content and oxygen metabolism alterations. This study aims to investigate subcortical alterations of susceptibility-derived metrics in these two synucleinopathies. Methods: A cohort comprising 180 patients (122 with PD and 58 with MSA) and 77 healthy controls (HCs) underwent clinical evaluation and multi-echo gradient echo MRI scans. Susceptibility source separation, susceptibility-based oxygen extraction fraction (OEF) mapping and semiautomatic subcortical nuclei segmentation were utilized to derive parametric values of deep gray matter in all subjects. Results: MSA patients showed markedly elevated paramagnetic susceptibility values in the putamen, globus pallidus (GP) and thalamus; increased diamagnetic susceptibility values in the putamen and dentate nucleus; and reduced OEF values across all nuclei compared with PD patients and HCs. Whereas PD exhibited increased positive susceptibility values in the substantia nigra and enhancing negative values in the GP, similar to MSA. Notably, age-related reductions in OEF were evident in HCs, which was altered by the MSA pathology. Paramagnetic susceptibility was correlated with disease severity. Moreover, the susceptibility-derived metrics of striatum and midbrain nuclei proved to be effective predictors to distinguish PD from MSA (AUC = 0.833). Conclusion: Susceptibility-derived metrics could detect pathological involvement distinct to each disease, offering significant potential for differentiating between MSA and PD in clinical settings.