Transcriptomic and neurotransmitter correlates of structure and function spatial variations patterns in spinocerebellar Ataxia.

BACKGROUND

Spinocerebellar ataxia (SCA) is characterized by cortical structural and functional impairments, but the underlying biological mechanisms remain poorly understood.

METHODS

We applied T1-weighted magnetic resonance imaging (MRI) and resting-state functional MRI (fMRI) to investigate cortical alterations in 49 SCA patients and 48 matched controls. Cortical thickness and amplitude of low-frequency fluctuations (ALFF) were quantified and compared with spatial maps of 19 neurotransmitter systems. Gene expression patterns were examined using partial least squares regression, followed by gene ontology analysis to identify associated biological processes.

RESULTS

Both cortical thickness and ALFF emerged as sensitive biomarkers of cortical impairment in SCA. Thickness alterations were strongly associated with disruptions in cholinergic, serotonergic, and glutamatergic systems. ALFF alterations were linked to toxin-response and detoxification processes, with relevant gene expression enriched in astrocytes.

CONCLUSION

Our convergent imaging-transcriptomic analysis integrates direct molecular vulnerability and CTC-based transsynaptic degeneration, yielding a unified systems-level view of SCA. These findings go beyond correlation by prioritizing molecular pathways and non-neuronal cellular targets and enabling network-informed prediction of additional vulnerable regions.