Aberrant connectivity of lateral prefrontal networks in presymptomatic Huntington's disease

In clinically presymptomatic individuals with the Huntington's disease (HD) gene mutation, functional neuroimaging data have suggested a dysfunction of multiple cortical and subcortical regions including the prefrontal and parietal cortex, as well as the striatum. Although it has been hypothesized that these activation differences most likely reflect aberrant corticostriatal circuits, the functional coupling of neural networks associated with cognitive performance has not been investigated so far. In this study, we used functional magnetic resonance imaging (fMRI) and multivariate analytic techniques to investigate memory-related patterns of functional connectivity in healthy controls (n = 16) and pre-HD individuals (n = 16). Independent component analyses (ICA) revealed distinct bilateral frontostriatal and frontoparietal networks that were activated during a verbal working memory paradigm in both healthy controls and pre-HD subjects. Compared with healthy controls, pre-HD individuals exhibited lower functional connectivity in left lateral prefrontal and parietal regions as well as in the bilateral putamen. Functional connectivity indices in the left putamen were negatively correlated with the CAG repeat size and the UHDRS behavioral score, and positively correlated with the predicted years to manifest symptom onset. The connectivity of the right putamen was negatively correlated with the UHDRS motor score. In pre-HD individuals, these results suggest an early frontostriatal and frontoparietal deficit of dissociable functional networks associated with executive processing.