Cerebellar and Brainstem White Matter Geometric Alterations in Multiple System Atrophy: A DFA ‐Based Biomarker for Disease Staging

Aims To characterize white matter geometric pathology in cerebellar subtype of multiple system atrophy (MSA‐C) using director field analysis (DFA) and identify stage‐specific biomarkers. Methods We analyzed single‐shell diffusion MRI ( b = 1000) in 31 MSA‐C patients (15 early‐, 16 late‐stage) and 33 controls. DFA quantified axonal geometry (splay/bend/twist), complemented by fixel‐based analysis (FBA) and brainstem volumetry. Group comparisons used threshold free cluster enhancement (TFCE) ( p < 0.05 FWE‐corrected). DFA‐altered regions were correlated with clinical scores. AutoGluon evaluated classification performance using different feature sets. Results MSA‐C exhibited distinct geometric degeneration patterns: cerebellar pathways showed reduced splay, bend, and twist (reflecting Wallerian degeneration), whereas brainstem tracts demonstrated dissociated geometry (increased splay/bend but decreased twist). Brainstem twist reduction strongly differentiated early‐ and late‐stage MSA‐C (AUC = 0.95). Clinically, middle cerebellar peduncle bend correlated with motor progression (UMSARS‐II: r = 0.48), while cerebellar splay reduction predicted ataxia severity (SARA: r = −0.43). Conclusion DFA captures circuit‐specific white matter pathology in MSA‐C, with brainstem twist emerging as a novel biomarker associated with disease stage. The integration of geometric metrics with automated machine learning provides a robust framework for early diagnosis and disease staging, highlighting distinct neurodegenerative mechanisms in cerebellar versus brainstem pathways.