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

Area of Science:

• Neuroimaging
• Neurodegenerative Diseases
• Neuroanatomy

Background:

• Cholinergic system dysfunction is key in Multiple System Atrophy (MSA) pathophysiology.
• In vivo characterization of nucleus basalis of Meynert (NBM) and pedunculopontine nucleus (PPN) pathways in MSA is limited.
• Understanding these pathways' clinical relevance is crucial for MSA management.

Purpose of the Study:

• To use diffusion MRI and free-water (FW) imaging to assess cholinergic system degeneration in MSA.
• To investigate the association between cholinergic pathway integrity and clinical features in MSA patients.

Main Methods:

• Diffusion MRI and FW imaging were performed on 103 MSA patients and 44 controls.
• Probabilistic tractography reconstructed medial NBM, lateral NBM, and PPN-thalamus pathways.
• Free-water fraction (FWf) and corrected axial diffusivity (cAxD) quantified microstructural integrity.

Main Results:

• MSA patients exhibited higher FWf in lateral NBM and PPN-thalamus pathways compared to controls.
• An FWf-based model achieved high accuracy (AUC=0.89) in differentiating MSA patients, with PPN-thalamus FWf being most discriminative.
• Increased FWf in all pathways correlated with longer disease duration; PPN-thalamus FWf correlated with Unified MSA Rating Scale scores.

Conclusions:

• Cholinergic pathway degeneration is a significant feature of MSA.
• The PPN-thalamus pathway is particularly vulnerable and clinically relevant in MSA.
• Elevated FWf suggests neuronal degeneration or neuroinflammation linked to alpha-synuclein pathology.