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Diffusion tensor imaging in male premutation carriers of the fragile X mental retardation gene

Authors

  • Ryu-ichiro Hashimoto PhD,

    1. Center for Mind and Brain, University of California, Davis, Davis, California, USA
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  • Siddharth Srivastava PhD,

    1. Medical Investigation of Neurodevelopmental Disorder (MIND), University of California, Davis, Sacramento, California, USA
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  • Flora Tassone PhD,

    1. Medical Investigation of Neurodevelopmental Disorder (MIND), University of California, Davis, Sacramento, California, USA
    2. Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, California, USA
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  • Randi J. Hagerman MD,

    1. Medical Investigation of Neurodevelopmental Disorder (MIND), University of California, Davis, Sacramento, California, USA
    2. Department of Pediatrics, University of California, Davis Medical Center, Sacramento, California, USA
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  • Susan M. Rivera PhD

    Corresponding author
    1. Center for Mind and Brain, University of California, Davis, Davis, California, USA
    2. Medical Investigation of Neurodevelopmental Disorder (MIND), University of California, Davis, Sacramento, California, USA
    3. Department of Psychology, University of California, Davis, Davis, California, USA
    • Center for Mind and Brain, 202 Cousteau Place, Suite 250, Room 245, Davis, CA 95618, USA

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  • Relevant conflicts of interest/financial disclosures: The study was funded by NIH grants UL1DE019583, DA024854, and HD036071, NINDS grant RL1NS062412, and NIA grants RL1AG032119, RL1AG032115, and NCRR UL1 RR024146. Dr. Hagerman has received funding from Roche, Novartis, Seaside Therapeutics, Forest, Johnson and Johnson, and Neuropharm for treatment trials in fragile X or autism. There are no other potential conflicts of interest to report.

    Full financial disclosures and author roles may be found in the online version of this article.

Abstract

Older male premutation carriers of the FMR1 gene are associated with the risk of developing a late-onset neurodegenerative disorder, fragile X–associated tremor/ataxia syndrome. Although previous postmortem and in vivo magnetic resonance imaging studies have indicated white matter pathology, the regional selectivity of abnormalities, as well as their relationship with molecular variables of the FMR1 gene, has not been investigated. In this study, we used diffusion tensor imaging to study male premutation carriers with and without fragile X–associated tremor/ataxia syndrome and healthy sex-matched controls. We performed a tract of interest analysis for fractional anisotropy and axial and radial diffusivities of major white matter tracts in the cerebellar–brain stem and limbic systems. Compared with healthy controls, patients with fragile X–associated tremor/ataxia syndrome showed significant reductions of fractional anisotropy in multiple white matter tracts, including the middle cerebellar peduncle, superior cerebellar peduncle, cerebral peduncle, and the fornix and stria terminalis. Significant reduction of fractional anisotropy in these tracts was confirmed by voxel-wise analysis using tract-based spatial statistics. Analysis of axial and radial diffusivities showed significant elevation of these measures in middle cerebellar peduncle, even among premutation carriers without fragile X–associated tremor/ataxia syndrome. Furthermore, regression analyses demonstrated a clear inverted U-shaped relationship between CGG-repeat size and axial and radial diffusivities in middle cerebellar peduncle. These results provide new evidence from diffusion tensor imaging for white matter abnormalities in the cerebellar–brain stem and limbic systems among individuals with the fragile X premutation and suggest the involvement of molecular mechanisms related to the FMR1 gene in their white matter pathology. © 2011 Movement Disorder Society

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