Objective: To determine whether alterations in cholinergic functional connectivity (FC) in early PD relate to the intrinsic organization of the basal forebrain (BF) functional connectome.

Background: The BF cholinergic system projects widely to the cortex and plays a key role in cognition.[1, 2] Pathological changes to the nucleus basalis of Meynert (NBM; Ch4) occur early in PD[2, 3], but whether disease-related FC alterations are spatially diffuse or follow the topography of BF cortical connectivity remains unknown.

Method: Resting-state fMRI from 302 PD (duration 1.1±1.7 years) and 64 healthy control (HC) subjects was analyzed.[4] FC was estimated between each BF voxel and 400 cortical parcels and used to derive BF gradients via diffusion map embedding.[5] The principal gradient reflecting a continuous axis of BF-cortex FC (45% of variance explained) was selected for analysis (Fig 1A). Gradient-weighted cortical maps were generated per subject, with the HC mean serving as the normative template (Fig 1B). Subregional FC differences were correlated with geodesic distance and normative gradient expression using spin-permutation testing. Individual alignment to the normative template was correlated with motor severity and cognition.

Results: PD patients showed reduced Ch4 FC with the anterior insula, cingulate, anteromedial temporal and prefrontal regions and increased FC with somatomotor and visual regions (Fig 1C). Effect maps scaled with geodesic distance (r=0.50, p=0.001, Fig 1D) and demonstrated a relationship with BF gradient cortical expression (r=−0.27, p=0.008, Fig 1E). More distal regions showed relative hyperconnectivity, whereas proximal regions showed greater hypoconnectivity, with FC changes varying systematically with gradient position. These effects were not observed for Ch1-3, suggesting specificity to NBM dysfunction. Within PD, alignment predicted executive (ρ=0.21, p<0.001), attention (ρ=0.12, p=0.04) and visuospatial (ρ=0.13, p=0.02) function but not global cognition (MoCA) or motor severity (MDS-UPDRS III).

Conclusion: Altered NBM FC in PD is structured by both anatomical distance and the BF functional gradient, with loss of normal cortical gradient expression associated with poorer domain-specific cognition. These findings suggest that cholinergic vulnerability in early PD is reflected in the global architecture of BF connectivity and is detectable even before overt cognitive decline.

Figure 1

References: 1. Zaborszky, L., et al., Neurons in the Basal Forebrain Project to the Cortex in a Complex Topographic Organization that Reflects Corticocortical Connectivity Patterns: An Experimental Study Based on Retrograde Tracing and 3D Reconstruction. Cerebral Cortex, 2013. 25(1): p. 118-137.
2. Bohnen, N.I., et al., Cholinergic system changes in Parkinson’s disease: emerging therapeutic approaches. Lancet Neurol, 2022. 21(4): p. 381-392.
3. Liu, A.K., et al., Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer’s and Parkinson’s disease. Acta Neuropathol, 2015. 129(4): p. 527-40.
4. Parkinson’s Progression Markers Initiative. Parkinson’s Progression Markers Initiative (PPMI). Accessed February 28, 2026; https://www.ppmi-info.org.
5. Chakraborty, S., et al., Multimodal gradients of basal forebrain connectivity across the neocortex. Nature Communications, 2024. 15(1): p. 8990.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cholinergic-dysconnectivity-in-early-parkinsons-disease-aligns-with-the-basal-forebrain-functional-gradient/