title: Prefrontal executive function associated coupling relates to Huntington's disease stage.
abstract: Huntington's disease (HD) is a neurodegenerative disease caused by cytosine-adenine-guanine (CAG)-repeat expansion in the huntingtin (HTT) gene. Early changes that may precede clinical manifestation of movement disorder include executive dysfunction. The aim of this study was to identify functional network correlates of impaired higher cognitive functioning in relation to HD stage. Blood-oxygenation-level-dependent (BOLD) functional-magnetic resonance imaging (fMRI) and structural-MRI were performed in 53 subjects with the HD-mutation (41 prodromals, 12 early affected) and 52 controls. Disease stage was estimated for each subject with HD-mutation based on age, length of the CAG-repeat expansion mutation and also putaminal atrophy. The Tower of London test was administered with three levels of complexity during fMRI as a challenge of executive function. Functional brain networks of interest were identified based on cortical gray matter voxel-clusters with significantly enhanced task-related functional coupling to the medial prefrontal cortex (MPFC) area. While prodromal HD-subjects showed similar performance levels as controls, multivariate analysis of task-related functional coupling to the MPFC identified reduced connectivity in prodromal and early manifest HD-subjects for a cluster including mainly parts of the left premotor area. Secondary testing indicated a significant moderator effect for task complexity on group differences and on the degree of correlation to measures of HD stage. Our data suggest that impaired premotor-MPFC coupling reflects HD stage related dysfunction of cognitive systems involved in executive function and may be present in prodromal HD-subjects that are still cognitively normal. Additional longitudinal studies may reveal temporal relationships between impaired task-related premotor-MPFC coupling and other brain changes in HD.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Division of Psychiatry Research and Psychogeriatric Medicine, University of Zürich, Zürich, Switzerland. Electronic address: paul.unschuld@uzh.ch.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Unschuld
authors.forename: Xinyang
authors.initials: X
authors.lastname: Liu
authors.forename: Megan
authors.initials: M
authors.lastname: Shanahan
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
authors.forename: Susan S
authors.initials: SS
authors.lastname: Bassett
authors.forename: Jason
authors.initials: J
authors.lastname: Brandt
authors.forename: David J
authors.initials: DJ
authors.lastname: Schretlen
authors.forename: Graham W
authors.initials: GW
authors.lastname: Redgrave
authors.forename: Jun
authors.initials: J
authors.lastname: Hua
authors.forename: Christoph
authors.initials: C
authors.lastname: Hock
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Reading
authors.forename: Peter C M
authors.initials: PC
authors.lastname: van Zijl
authors.forename: James J
authors.initials: JJ
authors.lastname: Pekar
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
mesh_terms: D000328:Adult; D001931:Brain Mapping; D018450:Disease Progression; D056344:Executive Function / Q000502:physiology*; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000503:physiopathology / Q000523:psychology*; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D017397:Prefrontal Cortex / Q000503:physiopathology*; D011597:Psychomotor Performance / Q000502:physiology; D011930:Reaction Time / Q000502:physiology
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010100:Oxygen
keywords: Cognition; Cortical networks; Executive function; Functional connectivity; Huntington's disease; Neurodegeneration; fMRI