Decoding the Clinical-Radiological Paradox: Brain Network Mechanisms in Spinocerebellar Ataxia Type 3 Revealed

On August 17, the team of Professor Liu Chen and Professor Wang Jian from the Department of Radiology at Southwest Hospital of Army Medical University, in collaboration with Professor Long Zhiliang's team from the Faculty of Psychology at Southwest University, systematically revealed for the first time the micro-level molecular pathological mechanisms underlying macroscopic brain network decoupling in patients with spinocerebellar ataxia type 3 (SCA3) by integrating multimodal magnetic resonance imaging technology with high-resolution micro-biological atlases. This provides a novel perspective and objective imaging targets for resolving the "clinical-radiological dissociation" challenge in clinical diagnosis and treatment. The findings were published in the internationally leading journal in the field of movement disorders, *Movement Disorders*, under the title "Putaminal Structure-Function Decoupling as an Early Candidate Imaging Biomarker for Motor Severity in Spinocerebellar Ataxia Type 3."

"Spinocerebellar ataxia type 3 is the most common autosomal dominant hereditary ataxia worldwide, caused by abnormal expansion of the CAG (cytosine-adenine-guanine) repeat sequence in the ATXN3 (ataxin-3) gene, which severely impairs patients' motor function," Liu Chen explained. In long-term clinical practice, physicians often face a challenging dilemma—the clinical-radiological dissociation phenomenon, where the degree of macroscopic brain structural atrophy often fails to fully explain the severity of clinical motor symptoms.

"More critically, although the academic community has recognized the role of abnormal brain structural and functional connectivity in neurodegenerative diseases, the maintenance of synchronized neural activity requires not only physical structural connectivity support but also efficient mitochondrial energy supply and precise synaptic regulation. How these micro-level molecular pathologies ultimately drive macroscopic imaging phenotype changes had not been systematically elucidated prior to this study," Liu Chen stated.

To investigate this core mechanism, the research team conducted a hypothesis-driven prospective dual-center multimodal imaging study, enrolling a large cohort of genetically confirmed SCA3 patients and healthy controls. Using cutting-edge algorithms, they quantified the "structure-function coupling" index of participants' brains—the degree of synergistic matching between physical brain structural connectivity and actual neural activity function. Building on this, the team performed spatial mapping analyses correlating macroscopic brain network coupling changes with the latest brain mitochondrial proteomic atlas, the Allen Human Brain Transcriptomic Atlas, and PET-based neurotransmitter receptor atlases. This cutting-edge imaging-transcriptomic cross-analysis approach successfully bridged macroscopic neuroimaging phenotypes and micro-level molecular pathology at the in vivo level.

"The study found that SCA3 patients exhibit significant structure-function connectivity decoupling independent of brain atrophy at early disease stages, and the degree of decoupling is highly correlated with the severity of clinical ataxia symptoms," Liu Chen noted. The team also precisely identified the core brain region—the bilateral dorsolateral putamen—whose abnormal signals demonstrate both sensitivity and stability, potentially serving as a convenient imaging "ruler" to assist physicians in early quantification of motor impairment progression. More importantly, the study confirmed that this macroscopic network disruption does not occur randomly but deeply overlaps with intrinsic vulnerable regions at the micro-level, including mitochondrial complex II regulating energy metabolism, 5-hydroxytryptamine 2A receptor/5-hydroxytryptamine 4 receptor densities affecting neural transmission, and gene expression-enriched regions responsible for synaptic plasticity and cellular homeostasis regulation.

"These findings provide clinically objective and precise imaging targets reflecting early SCA3 pathology, confirm for the first time that brain network decoupling is one of the core early pathological features of SCA3, and elucidate the underlying micro-level genetic, mitochondrial functional, and neurotransmitter receptor mechanisms, greatly deepening the medical community's understanding of SCA3 pathogenesis," Liu Chen said.

In the next step, the research team plans to conduct larger-scale multicenter long-term follow-up studies to further validate the reliability and clinical generalizability of the "bilateral dorsolateral putamen structure-function decoupling" imaging biomarker across a broader patient population.