This human neuroimaging study reports reduced locus coeruleus neuromelanin signal in PD and subtype-specific directional effective connectivity patterns between the LC, cerebellum, and cortical regions that correlate with motor severity in tremor-dominant versus akinetic-rigid patients.

It identifies a noninvasive LC biomarker and subtype-specific functional signatures that could inform patient stratification and development of noradrenergic-targeted or personalized neuromodulation therapies in Parkinson's disease.

OBJECTIVE: The involvement of locus coeruleus (LC) in Parkinson's disease (PD) motor dysfunction remains unclear. This study aims to investigate LC's directional influence on the whole-brain in tremor-dominant (TD) and akinetic-rigid (AR) PD. METHODS: Forty-nine PD patients (20 TD and 29 AR) and 20 healthy controls (HCs) from a single center were retrospectively analyzed. The contrast-to-noise ratio (CNR) of LC was assessed using Neuromelanin-sensitive MRI. Effective connectivity (EC) of the LC was analyzed using seed-based Granger Causality analysis to examine the inflow and outflow of the LC's directional influence using functional MRI, corrected by Gaussian random field at voxel level (P < 0.01) and cluster level (P < 0.05). Pearson's analysis assessed the correlation between EC results and MDS-UPDRS III (P < 0.05, Bonferroni corrected). RESULTS: The CNRLC was significantly lower in both PD subgroups than in HCs, with TD-PD showing higher CNRLC than AR-PD. Compared to HCs, TD-PD exhibited enhanced EC from the LC to the cerebellum and inferior temporal gyrus; and from the cerebellum to the LC.AR-PD exhibited enhanced EC from the LC to the inferior temporal gyrus and cerebellum. Compared to TD-PD, AR-PD exhibited stronger EC from the LC to the middle frontal, inferior frontal, and middle occipital gyri, and from the cerebellum to the LC. LC-EC correlated significantly with MDS-UPDRS III in TD-PD and AR-PD (R = -0.487 to 0.682, P = 0.001 to 0.007). CONCLUSION: Our results highlight the LC's directional influence in TD-PD and AR-PD, providing insights into motor dysfunction that could inform LC-noradrenaline-based therapy for personalized intervention.