Longitudinal changes in the fronto-striatal network are associated with executive dysfunction and behavioral dysregulation in Huntington's disease: 30 months IMAGE-HD data

Neuropsychiatric disturbance−particularly executive dysfunction and behavioral dysregulation−is a common feature of Huntington's disease (HD), with implications for functional capacity and quality of life. No study to date has ascertained whether longitudinal change in brain activity is associated with neuropsychiatric deficits in HD. We used a set-response-shifting task together with functional magnetic resonance imaging to investigate 30-month longitudinal blood-oxygen level dependent (BOLD) signal changes in the fronto-striatal attentional control network in premanifest and symptomatic HD (pre-HD and symp-HD, respectively), relative to healthy control participants. We also assessed the extent to which changes in the BOLD signal over time were related to neuropsychiatric measures in the domains of executive dysfunction and behavioral dysregulation. Associations were also evaluated with clinical and disease severity. We found no longitudinal BOLD differences between pre-HD and controls over 30 months. In contrast, reduction in BOLD response over time was greater in symp-HD, relative to controls, in task-related areas (e.g., anterior cingulate cortex and striatum) and in regions from the default mode network (e.g., medial prefrontal cortex and posterior cingulate/precuneus). Moreover, when considered across both premanifest and symptomatic stages, longitudinal BOLD signal decline in the right dorsolateral prefrontal cortex and putamen was associated with executive dysfunction and behavioral dysregulation measures. In addition, longitudinal reduction in BOLD signal, in fronto-striatal and default mode networks, correlated with disease severity. These results suggest that longitudinal change in fronto-striatal and default mode networks may be useful in understanding the biological underpinnings of functional decline in HD. Such findings offer new avenues for targeted treatments in terms of minimizing psychiatric impairment and potentially maximizing cognitive function.