title: White matter integrity in premanifest and early Huntington's disease is related to caudate loss and disease progression.
abstract: BACKGROUND
  Huntington's disease (HD) is associated with progressive loss of caudate and white matter volume and integrity. Our aim was to systematically assess interactions between these changes and genetic markers of disease progression; we are not aware of previous studies in which this has been explicitly tested.
  
  
  METHODS
  Tract-based spatial statistics were used to assess: (a) differences between the white matter diffusion metrics (fractional anisotropy and mean diffusivity) of 17 premanifest and 19 early manifest HD gene carriers and 21 controls, and (b) the relationships between diffusion metrics, caudate and total white matter volume, and disease burden score and CAG repeat length. Caudate and total white matter volumes were quantified using FIRST and SIENAX respectively. Multiple regression analysis was used to assess which of the imaging metrics predicted disease severity in the HD subjects.
  
  
  RESULTS
  Diffusion metrics were significantly altered in premanifest and early HD gene carriers in comparison with controls throughout the white matter skeleton. Correlations between diffusion and volumetric metrics and disease progression were also present. Together, caudate volume and mean white matter fractional anisotropy and mean diffusivity predicted disease burden score in the HD subjects.
  
  
  CONCLUSIONS
  The diffusion properties of white matter are extensively altered in HD, and are associated with markers of HD severity, and with caudate and white matter volumes. The correlation between diffusion metrics and white matter volume is stronger in HD subjects than in controls, but there is no such significant interaction for the correlation between diffusion and caudate volume: we propose that many of the changes in white matter diffusion in HD occur as a 'normal' physiological response to pathological caudate volume loss. We have defined the extent to which mean white matter fractional anisotropy, white matter volume and caudate volume are associated with disease burden score.
authors.affiliation: National Hospital for Neurology and Neurosurgery, London, UK; Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, London, UK.
authors.forename: Marianne J U
authors.initials: MJ
authors.lastname: Novak
authors.affiliation: Imaging and Biophysics Unit, UCL Institute of Child Health, London, UK.
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Seunarine
authors.affiliation: Imaging and Biophysics Unit, UCL Institute of Child Health, London, UK; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Clare R
authors.initials: CR
authors.lastname: Gibbard
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Nicola Z
authors.initials: NZ
authors.lastname: Hobbs
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
authors.forename: Rachael I
authors.initials: RI
authors.lastname: Scahill
authors.affiliation: Imaging and Biophysics Unit, UCL Institute of Child Health, London, UK. Electronic address: christopher.clark@ucl.ac.uk.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Clark
authors.affiliation: National Hospital for Neurology and Neurosurgery, London, UK; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. Electronic address: s.tabrizi@prion.ucl.ac.uk.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
mesh_terms: D000328:Adult; D001284:Atrophy / Q000473:pathology; D002421:Caudate Nucleus / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D059906:Neuroimaging; D009929:Organ Size
keywords: Caudate; DTI (diffusion tensor imaging); Diffusion; Huntington's disease; TBSS (tract-based spatial statistics)