Membrane and bioenergetic dysfunction in Parkinson's disease with REM sleep behavior disorder: A ³¹P and ¹H MR study

REM sleep behavior disorder (RBD) in Parkinson's disease (PD) marks a more aggressive subtype. While mitochondrial dysfunction, iron deposition, and neuromelanin loss are central to PD pathobiology, their contributions to RBD in PD remain unclear. This study noninvasively compared brain bioenergetics, phospholipid metabolism, iron accumulation, and neuromelanin integrity across PD patients with RBD (PD-RBD), without RBD (PD-noRBD), and healthy controls (HCs) to identify RBD-related metabolic alterations. Twenty-six PD-RBD, 46 PD-noRBD, and 48 HCs were recruited consecutively. All participants underwent 3T MRI, including phosphorus-31 MR spectroscopic imaging (³¹P-MRSI), quantitative susceptibility mapping (QSM), and neuromelanin-sensitive MRI (NM-MRI), all acquired in a standardized OFF-medication state (≥12 h withdrawal). Phosphorus metabolites included phosphoethanolamine (PE), total adenosine triphosphate (tATP), phosphodiester (PDE), and others. Group differences and associations with clinical scales were analyzed, and PD subtype discrimination performance was assessed using ROC analysis. PD-RBD patients demonstrated right basal ganglia metabolic alterations characterized by elevated α-ATP/Pi (p = 0.003 vs HCs) and PCr/Pi ratios (p = 0.001 vs HCs), together with reduced PE-related phospholipid turnover indices, including lower PE/tATP relative to PD-noRBD (p = 0.003). In contrast, PD-noRBD showed milder alterations primarily involving high-energy phosphate metabolism compared with HCs, whereas phospholipid turnover remained relatively preserved. No significant differences in iron or neuromelanin measures were observed between PD-RBD and PD-noRBD groups. However, both PD subgroups showed significantly reduced neuromelanin-related contrast in the substantia nigra compared to HCs. PE/tATP (R = -0.350, p < 0.01) and PE/PDE ratios (R = -0.441, p < 0.001) were negatively correlated with RBD symptom severity across the PD cohort. ³¹P-MRSI demonstrated superior discrimination performance (AUC = 0.80) compared with QSM (AUC = 0.72) or NM-MRI (AUC = 0.69), while multimodal integration achieved the highest diagnostic accuracy (AUC = 0.86). These findings support a role for altered bioenergetic and membrane phospholipid metabolism in PD-RBD and highlight ³¹P-MRSI as a promising imaging approach for characterizing PD heterogeneity.