Cholinergic network disruptions on cognitive function across the spectrum of cognitive impairment in Parkinson's...

Cognitive decline in Parkinson's disease (PD) is closely associated with degeneration of the cholinergic system; however, the stage-dependent reorganization of cholinergic networks remains poorly understood. This study aimed to delineate alterations in cholinergic connectivity across the spectrum of cognitive impairment in PD patients.

We enrolled 211 PD patients-classified as PD with normal cognition (PD-NC, n = 91), mild cognitive impairment (PD-MCI, n = 79), or dementia (PDD, n = 41)-and 71 healthy controls (HCs). Cholinergic functional networks were reconstructed by mapping predefined cholinergic subnetwork maps onto individual resting-state functional MRI data to derive subject-specific functional connectivity matrices. Graph theoretical measures were applied to quantify global and local topological characteristics. In addition, voxel-based morphometry (VBM) was used to assess group differences in cholinergic nuclei volumes. Furthermore, correlation and mediation analyses were conducted to explore the relationship between network disruption and cognitive performance.

PD patients showed stage-dependent alterations in cholinergic network topology, with increased shortest path length (Lp) and global efficiency in the Ch1-3 pathway and reduced clustering coefficient, gamma, Lp, and sigma in the medial Ch4 pathway (p < 0.05). Regionally, right hippocampal nodal centrality (Ch1-3) and inferior occipital gyrus/local efficiency (Ch4 lateral capsular division) were reduced in PDD, while posterior orbital part of the right medial superior frontal gyrus (medial Ch4) degree centrality increased. Medial Ch4 topological brain metrics correlated with global cognition and key domains, whereas metrics of Ch4 lateral capsular division pathway related to visuospatial and language performance. Structurally, compared to HCs, Ch4 volume loss occurred in PD-NC and PD-MCI groups, while Ch5-6 atrophy was specific in PDD group. Mediation analysis confirmed that medial Ch4 Lp mediated the effect of disease stage on global cognition.

This study provides new insights into the stage-specific disruption of cholinergic network topology and structural atrophy in PD, demonstrating that Ch4 nucleus degeneration is critically associated with stage-dependent network dysfunction and domain-specific cognitive impairment, thereby offering cholinergic network biomarkers as potential tools for stratifying cognitive stages.