Potential functional compensation of substantia nigra by locus coeruleus in Parkinson’s disease

Abstract Neuromelanin is abundant in locus coeruleus (LC), yet its loss occurs across multiple neurodegenerative diseases. However, the role of LC in Parkinson’s disease (PD) remains controversial. In this study, we recruited 37 patients with PD, 18 patients with mild cognitive impairment (MCI), and 27 healthy controls (HC). All participants underwent clinical assessments and multimodal MRI acquisition. Neuromelanin-sensitive MRI (NM-MRI) was used to quantify neuromelanin loss in substantia nigra pars compacta (SNpc) and LC, while 3D T1-weighted imaging and BOLD-fMRI were employed to assess structural and functional brain networks, respectively. Voxel-based and surface-based morphometry revealed PD was primarily associated with impairments in visual, control, and somatomotor network, whereas MCI predominantly involved dysfunction of default mode network. The contrast-to-noise ratio in both SNpc and LC was significantly reduced in PD. In contrast, MCI patients showed no apparent SNpc alterations but exhibited significant neuromelanin loss in LC. Graph theory analysis demonstrated pathological hyper-efficiency in the functional connectivity network of PD, with compensatory or maladaptive nodal changes varying across disease-related networks. Network-level analysis indicated that the effects of SNpc pathology on cortical morphological similarity and functional connectivity were complementary during PD progression. Moreover, LC exerted a functional compensatory influence on SNpc in PD, while SNpc showed particularly strong coupling with cortical morphological similarity in visual network. Hidden Markov model analysis further revealed PD was characterized by a reduced number of dynamic brain network states and a decreased state-switching rate, which was more strongly modulated by LC pathology. Collectively, these findings suggest that LC plays a substantial functional compensatory role for substantia nigra in PD.