Spatial Coupling between Parkinson’s Disease-Related Quantitative MRI Alterations and Mitochondrial Brain Architecture

Abstract Background and Objectives: Parkinson’s disease (PD) is a degenerative disease caused by multiple pathogenic processes, including mitochondrial dysfunction. Multiparametric mapping (MPM) provides insights into tissue biophysical properties but has limited biological specificity. We investigated whether the MPM-derived PD-related microstructural differences spatially overlap with the underlying brain’s mitochondrial architecture. Methods We performed MPM in 31 patients with idiopathic PD and 68 healthy controls, quantifying longitudinal relaxation rate (R1), effective transverse relaxation rate (R2*), proton density, and magnetic transfer saturation (MTsat). Using unthresholded group-differenced-derived t-maps, we performed spatial correlation with six mitochondrial brain atlas maps reflecting mitochondrial complex I, II, IV, mitochondrial density, and mitochondrial and tissue respiration capacity. Results Within gray matter, we observed weak but highly consistent spatial coupling between all four MPM modalities and mitochondrial features (all p FDR s ≤ 0.0004), with the strongest association with proton density (r = 0.265–0.320, p FDR = 0.0002–0.0003). Cortical motor areas and subcortical structures presented with region-specific MPM modality-mitochondrial feature association signatures. Discussion Our findings revealed region-specific spatial coupling between microstructural alterations and mitochondrial architecture in PD, providing in vivo evidence supporting a role for mitochondria in the spatial patterning of PD-related microstructural alterations.