Cortico-Basal Ganglia Interactions in Huntington’s Disease

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary movement, cognitive and psychiatric disturbances. The disease is caused by an expansion of polyglutamine repeats in the N-terminal domain of the huntington protein. Despite the single gene etiology, there is major variability in the neuropathology, as well as major heterogeneity in the symptom profiles. The major pathology occurs in the brain with profound degeneration in the forebrain regions, namely the basal ganglia and the cerebral cortex. In the basal ganglia, the progressive loss of striatal projection neurons, combined with the slow atrophy of other nuclei, were considered as the main neuropathological hallmarks of Huntington’s disease. However, it is now well established that the HD symptoms and brain dysfunction result from degeneration in both the cerebral cortex and basal ganglia. This review covers the main cortico-basal ganglia-thalamo-cortical circuits implicated in HD, specifically addressing the relationships between the cerebral cortex and striatum. Furthermore, this review explores the relationships between the pattern of cortical regional degeneration, striatal compartmental degeneration, and the combined contribution of these neuropathological features to the variable symptom phenotypes in HD. Based on the combined and variable contributions of cortical and sub-cortical regional cell loss in HD which links to the heterogeneous symptom profiles in HD patients, this review supports the notion of HD as a multi-system cortico-basal ganglia degenerative disease.