title: Large-scale brain network abnormalities in Huntington's disease revealed by structural covariance.
abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder that can be diagnosed with certainty decades before symptom onset. Studies using structural MRI have identified grey matter (GM) loss predominantly in the striatum, but also involving various cortical areas. So far, voxel-based morphometric studies have examined each brain region in isolation and are thus unable to assess the changes in the interrelation of brain regions. Here, we examined the structural covariance in GM volumes in pre-specified motor, working memory, cognitive flexibility, and social-affective networks in 99 patients with manifest HD (mHD), 106 presymptomatic gene mutation carriers (pre-HD), and 108 healthy controls (HC). After correction for global differences in brain volume, we found that increased GM volume in one region was associated with increased GM volume in another. When statistically comparing the groups, no differences between HC and pre-HD were observed, but increased positive correlations were evident for mHD, relative to pre-HD and HC. These findings could be explained by a HD-related neuronal loss heterogeneously affecting the examined network at the pre-HD stage, which starts to dominate structural covariance globally at the manifest stage. Follow-up analyses identified structural connections between frontoparietal motor regions to be linearly modified by disease burden score (DBS). Moderator effects of disease load burden became significant at a DBS level typically associated with the onset of unequivocal HD motor signs. Together with existing findings from functional connectivity analyses, our data indicates a critical role of these frontoparietal regions for the onset of HD motor signs.
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Freiburg, Germany.|Freiburg Brain Imaging Center, University Medical Center Freiburg, Freiburg, Germany.|Department of Psychology, Laboratory for Biological and Personality Psychology, University of Freiburg, Freiburg, Germany.
authors.forename: Lora
authors.initials: L
authors.lastname: Minkova
authors.affiliation: Department of Clinical Neuroscience and Medical Psychiatry, Heinrich-Heine University, Düsseldorf, Germany.|Research Center Jülich, Institute of Neuroscience and Medicine (INM-1), Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital, Jülich, Germany.
authors.forename: Simon B
authors.initials: SB
authors.lastname: Eickhoff
authors.affiliation: Freiburg Brain Imaging Center, University Medical Center Freiburg, Freiburg, Germany.|Department of Computer Science, University of Freiburg, Freiburg, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdulkadir
authors.affiliation: Freiburg Brain Imaging Center, University Medical Center Freiburg, Freiburg, Germany.|Department of Neurology, University Medical Center Freiburg, Freiburg, Germany.|BrainLinks-BrainTools Cluster of Excellence, University of Freiburg, Freiburg, Germany.
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Kaller
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Freiburg, Germany.|Freiburg Brain Imaging Center, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Peter
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Freiburg, Germany.|Freiburg Brain Imaging Center, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Scheller
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Freiburg, Germany.|Freiburg Brain Imaging Center, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Jacob
authors.initials: J
authors.lastname: Lahr
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands.
authors.forename: Raymund A
authors.initials: RA
authors.lastname: Roos
authors.affiliation: Department of Genetics and Cytogenetics, Pitié- Salpêtrière University Hospital, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.affiliation: Department of Neurodegenerative Disease, University College London, Institute of Neurology, London, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Freiburg, Germany.|Freiburg Brain Imaging Center, University Medical Center Freiburg, Freiburg, Germany.|Department of Neurology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Klöppel
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D001931:Brain Mapping; D003071:Cognition; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D008875:Middle Aged; D008959:Models, Neurological; D009068:Movement / Q000502:physiology; D009434:Neural Pathways / Q000473:pathology* / Q000503:physiopathology; D009483:Neuropsychological Tests; D012919:Social Behavior; D055815:Young Adult
keywords: Huntington's disease; MRI; Pearson's correlation; functional networks; grey matter volume; structural covariance