Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder characterized by progressive motor and nonmotor deficits concomitant with degenerative pathophysiological changes within the cerebellum. The cerebellum is topographically organized into cerebello‐cerebral circuits that create distinct functional networks regulating movement, cognition, and affect. SCA3‐associated motor and nonmotor symptoms are possibly related not only to intracerebellar changes but also to disruption of the connectivity within these cerebello‐cerebral circuits. However, to date, no comprehensive investigation of cerebello‐cerebral connectivity in SCA3 has been conducted. The present study aimed to identify cerebello‐cerebral functional connectivity alterations and associations with downstream clinical phenotypes and upstream topographic markers of cerebellar neurodegeneration in patients with SCA3. This study included 45 patients with SCA3 and 49 healthy controls. Voxel‐based morphometry and resting‐state functional magnetic resonance imaging (MRI) were performed to characterize the cerebellar atrophy and to examine the cerebello‐cerebral functional connectivity patterns. Structural MRI confirmed widespread gray matter atrophy in the motor and cognitive cerebellum of patients with SCA3. We found reduced functional connectivity between the cerebellum and the cerebral cortical networks, including the somatomotor, frontoparietal, and default networks; however, increased connectivity was observed between the cerebellum and the dorsal attention network. These abnormal patterns correlated with the CAG repeat expansion and deficits in global cognition. Our results indicate the contribution of cerebello‐cerebral networks to the motor and cognitive impairments in patients with SCA3 and reveal that such alterations occur in association with cerebellar atrophy. These findings add important insights into our understanding of the role of the cerebellum in SCA3.

Background Spinocerebellar ataxia type 3 (SCA3) is an inherited motor disorder that is characterized by low body mass index (BMI). Considering the role of the hypothalamus in regulating appetitive behaviors and metabolism, low BMI may result from hypothalamic degeneration. Objectives To examine hypothalamic volume changes in SCA3 by comparing patients and matched healthy controls and to identify potential mediating effects of hypothalamic pathology on CAG repeats for BMI. Methods Magnetic resonance imaging datasets of hypothalamic volumes from 41 SCA3 patients and 49 matched controls were analyzed. Relationships among CAG repeat number, hypothalamic volumes, and BMI were assessed using correlation and mediation analyses. Results SCA3 patients exhibited significant hypothalamic atrophy. Tubular hypothalamic volume was significantly associated with BMI. Mediation analysis revealed an indirect effect of CAG repeat number on BMI via tubular hypothalamic atrophy. Conclusions Low BMI in SCA3 is related to neurodegeneration within the tubular hypothalamus, providing a potential target for energy‐based treatment. © 2022 International Parkinson and Movement Disorder Society