Altered functional connectivity of dentate nucleus in parkinsonian and cerebellar variants of multiple system atrophy

The cerebellum is known to influence cerebral cortical activity via cerebello-thalamo-cortical (CTC) circuits and thereby may be implicated in the pathophysiology of multiple system atrophy (MSA). As the aim of this study, we investigated the abnormalities of corticocerebellar functional connectivity (FC) in patients with two variants of MSA. Resting-state functional magnetic resonance imaging (rs-fMRI) studies were obtained from 55 patients with MSA, including Parkinsonian (MSAp, n = 29) and cerebellar (MSAc, n = 26) variants. We also examined a similar number of healthy controls (HC, n = 51). Seed-based connectivity analysis was performed to assess alterations in CTC circuits. Relations between FC and clinical scores were assessed as well. Compared with the HC group, diminished FC was evident from bilateral dentate nucleus (DN) to motor cortex, bilateral basal ganglia, right cerebellum, default mode network (DMN), and limbic system in patients with MSAc. Patients with MSAp (vs HC subjects) showed less FC from left DN to right putamen, DMN, and limbic systems. Reduced FC was also demonstrated from left DN to DMN in patients with MSAc (vs MSAp), as well as from right DN to right cerebellum, DMN, basal ganglia, motor cortex, and limbic systems. In addition, the extent of FC from right DN to right cerebellum negatively correlated with Unified Parkinson's Disease Rating Scale-III scores in patients with MSA, while showing a positive association with Montreal Cognitive Assessment scores. The FC of DN was similarly altered in patients with MSAc and MSAp, although right cerebellar and motor cortical changes were more widespread in the MSAc group. There may be differing mechanisms of cerebellar functional activity responsible for motor and cognitive impairment, which should be further investigated.