Pathomechanisms of behavioral abnormalities in Huntington disease: an update

Huntington disease (HD), a devastating autosomal-dominant neurodegenerative disease caused by an expanded CAG trinucleotide repeat, is clinically characterized by a triad of symptoms including involuntary motions, behavior problems and cognitive deficits. Behavioral symptoms with anxiety, irritability, obsessive-compulsive behaviors, apathy and other neuropsychiatric symptoms, occurring in over 50% of HD patients are important features of this disease and contribute to impairment of quality of life, but their pathophysiology is poorly understood. Behavior problems, more frequent than depression, can be manifest before obvious motor symptoms and occur across all HD stages, usually correlated with duration of illness. While specific neuropathological data are missing, the relations between gene expression and behavior have been elucidated in transgenic models of HD. Disruption of interneuronal communications, with involvement of prefronto-striato-thalamic networks and hippocampal dysfunctions produce deficits in multiple behavioral domains. These changes that have been confirmed by multistructural neuroimaging studies are due to a causal cascade linking molecular pathologies (glutamate-mediated excitotoxicity, mitochondrial dysfunctions inducing multiple biochemical and structural alterations) and deficits in multiple behavioral domains. The disruption of large-scale connectivities may explain the variability of behavior profiles and is useful in understanding the biological backgrounds of functional decline in HD. Such findings offer new avenues for targeted treatments in terms of minimizing neurobehavioral impairment in HD.