Putamen Structural–Functional Decoupling as an Early‐Stage Candidate Imaging Marker for Motor Severity in Spinocerebellar Ataxia Type 3

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) shows marked phenotypic heterogeneity and clinico-radiological dissociation, wherein macrostructural atrophy often fails to fully account for clinical severity. Although structural and functional connectivity abnormalities are well recognized, their potential interaction and neurobiological mechanisms remain poorly understood. OBJECTIVE: This study aimed to identify potential biomarkers for SCA3 by linking structural connectivity-functional connectivity (SC-FC) coupling to mitochondrial function, neurotransmitter distribution, and gene expression. METHODS: This dual-center study included discovery (117 SCA3, 165 healthy controls [HC]) and independent validation (24 SCA3, 48 HC) cohorts. Participants underwent multimodal 3 T magnetic resonance imaging (MRI) and clinical assessments (Scale for the Assessment and Rating of Ataxia [SARA]; International Cooperative Ataxia Rating Scale [ICARS]; Montreal Cognitive Assessment [MoCA]; Hamilton Depression Rating Scale [HAMD]). Regional and network-level SC-FC coupling was quantified using multiple regression and compared across disease-duration strata. Coupling alterations were spatially mapped to biological atlases (Allen Human Brain Atlas, MitoBrainMap, and positron emission tomography [PET]-based neurotransmitter receptor atlases) using bootstrapped Spearman's correlations (false discovery rate [FDR]-corrected). Gene enrichment analysis was implemented to characterize enriched biological pathways. RESULTS: SCA3 patients exhibited significant, atrophy-independent SC-FC decoupling in the bilateral dorsolateral putamen (dlPu), which correlated with ICARS scores. This decoupling pattern spatially aligned with mitochondrial complex II, 5-HT2A/5-HT4 receptors densities, and genes enriching for synaptic regulation and cellular homeostasis. CONCLUSIONS: By integrating SC-FC coupling with biological atlases, this study reveals the pathological underpinnings of clinico-radiological dissociation in SCA3 and identifies dlPu decoupling as a promising early-stage candidate imaging marker, providing an early and objective target for future neuroprotective trials. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR): 1800019901, 2000039434. © 2026 International Parkinson and Movement Disorder Society.