Multimodal MRI Assessment of Cholinergic Basal Forebrain Degeneration Across Cognitive Stages in Parkinson's Disease

Abstract

Abstract Background Cognitive impairment in Parkinson's disease (PD) is linked to degeneration of the cholinergic basal forebrain, particularly cholinergic nucleus 4 (Ch4) in the nucleus basalis of Meynert. Structural and diffusion MRI separately detect this degeneration, but few studies have combined these modalities across the PD cognitive spectrum. Methods We analyzed 92 participants: 14 healthy controls (HC), 35 PD with normal cognition (PD-NC), 33 with mild cognitive impairment (PD-MCI), and 10 with dementia (PDD). For Ch4 and cholinergic nuclei 1, 2, and 3 (Ch1-3) in the medial septal/diagonal band complex, we determined TIV-normalized gray matter density (GMD) and free-water (FW) fraction. We evaluated group differences, cognitive correlations, adjusted multivariable regression, and exploratory ROC discrimination. Results Ch4 GMD was significantly lower in PDD compared to PD-MCI (p = 0.007), PD-NC (p < 0.001), and HC (p < 0.001). Ch4 GMD was also lower in PD-MCI versus HC (p = 0.028); the PD-MCI versus PD-NC difference was not significant after correction (p = 0.074). Ch1-3 GMD was lower in PDD versus PD-NC (p = 0.008) and HC (p = 0.009). Ch4 and Ch1-3 FW were elevated in PDD versus all other groups (all p < 0.01). Among PD patients (n = 78), MoCA was positively correlated with Ch4 GMD (ρ = 0.49) and Ch1-3 GMD (ρ = 0.42) and negatively correlated with Ch4 FW (ρ=−0.51) and Ch1-3 FW (ρ=−0.40; all p < 0.001). In the full four-metric model, Ch4 GMD and Ch4 FW were the only independent basal forebrain predictors (Ch4 GMD β=+2.04, p < 0.001; Ch4 FW β=−1.46, p = 0.005) of MoCA score. The combined Ch4 GMD + Ch4 FW model showed high discrimination for PDD versus non-demented PD (AUC = 0.934; optimism-corrected AUC = 0.925). Conclusions Structural and free-water diffusion MRI provide complementary information about Ch4 degeneration in PD. The combined Ch4 model showed promising exploratory discrimination of PDD; validation in larger independent samples is needed.

The authors' abstract, as published at the source. Parkinsonism & Related Disorders, 2026 · DOI ↗