Dissociation of Presynaptic and Postsynaptic Dopaminergic Associations with Microstructural Alterations in Parkinson’s Disease
Dissociation of Presynaptic and Postsynaptic Dopaminergic Associations with Microstructural Alterations in Parkinson’s Disease
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Original abstract
Abstract Background Parkinson’s disease (PD) is characterized by a degeneration of dopaminergic neurons not only in the nigrostriatal pathways, but also in subcortical and cortical structures. Given the widespread dopaminergic innervation, PD dopamine-related dysfunction may contribute to microstructural alterations beyond the primary site of pathology. Multiparametric mapping (MPM) enables quantification of the longitudinal relaxation rate (R1), the effective transverse relaxation rate (R2*), proton density, and magnetic transfer saturation (MTsat). We hypothesized that PD-related alterations in MPM would present with distinct spatial associations with pre- and postsynaptic dopaminergic markers. Methods 31 patients with PD (PwPD) and 68 healthy controls (HCs) underwent a 3T MRI. Subsequently, MPM maps (R2*, R1, proton density, and MTsat) were used for voxel-wise group differences analysis. We used unthresholded t-maps to assess spatial correlation with PET-derived maps of the dopamine transporter (DAT), [ 18 F]-fluoro-L-DOPA (FDOPA), and dopamine D1 and D2 receptors. Results We observed spatially consistent dissociation between presynaptic markers. DAT was predominantly negatively associated with all MPM alterations in PwPD, while FDOPA demonstrated positive associations. Subcortical regions demonstrated the strongest in magnitude, heterogeneous, and predominantly iron content (R2*)-related associations, specifically in the substantia nigra, ventral pallidum, and the nucleus accumbens. Cortical regions, in turn, exhibited more subtle yet highly consistent, neuroinflammation (proton density)-related spatial associations. The strongest associations were between proton density and DAT in the supplementary motor area (rho = -0.841, CI 95% = -0.844 to -0.837, p FDR = 0.0003) and presupplementary motor area (rho = -0.800, CI 95% = -0.803 to -0.796, p FDR = 0.0003). Conclusions The observed spatial dissociation between DAT- and FDOPA-MPM associations in subcortical regions indicates that microstructural degeneration is associated with the loss of dopaminergic terminals, while dopamine synthesis capacity remains preserved or may reflect compensatory responses. The cortical motor areas yielded more subtle, spatially consistent, and neuroinflammation-related association signatures, revealing differential association patterns between subcortical and cortical regions.