Brain Advance Access originally published online on December 3, 2007
Brain 2008 131(1):196-204; doi:10.1093/brain/awm275
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White matter connections reflect changes in voluntary-guided saccades in pre-symptomatic Huntington's disease
1Wellcome Trust Centre for Neuroimaging, Institute if Neurology, UCL, London, UK, 2Department of Neurology, Neurozentrum, University Clinic Freiburg, Freiburg, Germany, 3Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College London, UK, 4Department of Radiology, University of Pennsylvania, Philadelphia, USA, 5Department of Computer Science, UCL, London, 6Imaging Science and Biomedical Engineering, University of Manchester Manchester, 7Department of Clinical Neurology, Institute of Neurology, UCL, London, UK, 8Département d’études cognitives, Ecole Normale Supérieure, Paris, France and 9Laboratory of Neuroimaging, IRCCS Santa Lucia, Roma, Italy
Correspondence to: Stefan Klöppel MD; Department of Neurology; Breisacher Str. 64; 79106 Freiburg; Germany E-mail: stefan.kloeppel{at}uniklinik-freiburg.de
Huntington's disease is caused by a known genetic mutation and so potentially can be diagnosed many years before the onset of symptoms. Neuropathological changes have been found in both striatum and frontal cortex in the pre-symptomatic stage. Disruption of cortico-striatal white matter fibre tracts is therefore likely to contribute to the first clinical signs of the disease. We analysed diffusion tensor MR image (DTI) data from 25 pre-symptomatic gene carriers (PSCs) and 20 matched controls using a multivariate support vector machine to identify patterns of changes in fractional anisotropy (FA). In addition, we performed probabilistic fibre tracking to detect changes in ‘streamlines’ connecting frontal cortex to striatum. We found a pattern of structural brain changes that includes putamen bilaterally as well as anterior parts of the corpus callosum. This pattern was sufficiently specific to enable us to correctly classify 82% of scans as coming from a PSC or control subject. Fibre tracking revealed a reduction of frontal cortico-fugal streamlines reaching the body of the caudate in PSCs compared to controls. In the left hemispheres of PSCs we found a negative correlation between years to estimated disease onset and streamlines from frontal cortex to body of caudate. A large proportion of the fibres to the caudate body originate from the frontal eye fields, which play an important role in the control of voluntary saccades. This type of saccade is specifically impaired in PSCs and is an early clinical sign of motor abnormalities. A correlation analysis in 14 PSCs revealed that subjects with greater impairment of voluntary-guided saccades had fewer fibre tracking streamlines connecting the frontal cortex and caudate body. Our findings suggest a specific patho-physiological basis for these symptoms by indicating selective vulnerability of the associated white matter tracts.
Key Words: presymptomatic Huntington's disease; gene carriers; white matter; saccades
Abbreviations: AAL, automated anatomical labelling; BAs, Brodmann areas; DTI, diffusion tensor MR image; FA, fractional anisotropy; HD, Huntington's disease; PSCs, pre-symptomatic gene carriers; SVM, support vector machine; VBM, voxel-based morphometry
Received May 16, 2007. Revised October 1, 2007. Accepted October 5, 2007.
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