Abnormal Local Brain Activity in SCA3 Patients with Cognitive Impairment: A Resting-State Functional MRI Study

Cognitive impairment (CI) has been reported in spinocerebellar ataxia 3 (SCA3). However, the link between alterations in intrinsic brain activity and cognitive functions remains poorly understood. This study aimed to explore these alterations and their association with cognitive functions to elucidate the pathophysiological mechanisms underlying CI in SCA3. Eighty-four SCA3 patients and 41 healthy controls (HCs) were enrolled. Patients were classified into CI and non-CI groups based on their neuropsychological test performance relative to HCs. We calculated resting-state fMRI (rs-fMRI) metrics, including amplitude of low-frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), and degree centrality (DC), and compared them between the two patient groups. Whole-brain correlation analyses were used to explore the neural correlates of cognitive deficits by correlating rs-fMRI metrics with composite cognitive z-scores. Compared to SCA3 patients without CI, those with CI showed: (1) increased ALFF in fronto-striatal regions and decreased ALFF in the default mode network; (2) decreased fALFF in the dorsolateral prefrontal cortex but increased fALFF in the supplementary motor area and paracentral lobule; (3) increased ReHo in cerebellar cognitive regions; and (4) reduced DC in the left putamen, insula, and superior frontal gyrus. These alterations were primarily located within the cortico-striato-thalamo-cortical loop and cerebellar cognitive regions. Whole-brain correlation analyses confirmed that these rs-fMRI metric alterations correlated with cognitive performance. Our study revealed distinct patterns of spontaneous brain activity associated with cognitive impairment in SCA3. These findings provide novel imaging evidence for the pathophysiological mechanisms underlying cognitive decline in these patients.