Free-water imaging reveals cholinergic pathway damage in multiple system atrophy

Dysfunction of the cholinergic system is implicated in the pathophysiology of Multiple System Atrophy (MSA). However, in vivo assessment of cholinergic pathways originating from the nucleus basalis of Meynert (NBM) and pedunculopontine nucleus (PPN), and their clinical relevance remains inadequately characterized.

To utilize diffusion MRI and free-water (FW) image model to characterize cholinergic system degeneration in MSA and examine its association with clinical features.

We included 103 MSA patients and 44 healthy controls who underwent diffusion MRI. Probabilistic tractography reconstructed three major cholinergic pathways: a medial NBM projection via cingulum, a lateral NBM projection via external capsule, and PPN-thalamus pathway. FW imaging quantified microstructural integrity using FW fraction (FWf) and corrected axial diffusivity (cAxD). These DWI-based metric were analyzed to (1) differentiate patients from controls and (2) examine the associations with clinical features in MSA.

Compared to controls, MSA patients showed higher FWf values in both the lateral NBM and PPN-thalamus pathways. Receiver operating characteristic analysis showed that the FWf-based model best differentiated MSA from controls (AUC = 0.89 [0.76-1.00]), with PPN-thalamus FWf being the most discriminative feature. Across all three cholinergic pathways, higher FWf values were associated with longer disease duration, and PPN-thalamus FWf values specifically correlated with total Unified Multiple System Atrophy Rating Scale scores.

Cholinergic pathway damage is a prominent pathological feature of MSA, with PPN-thalamus pathway showing particular vulnerability (as indicated by increased FWf) and strong clinical relevance. This FWf elevation likely related to neuronal degeneration or neuroinflammatory changes driven by α-synuclein pathology.