A multimodal imaging analysis of subcortical gray matter in fragile X premutation carriers

Authors

  • Jun Yi Wang PhD,

    1. Center for Mind and Brain, University of California–Davis, Davis, California, USA
    2. Department of Psychiatry and Behavioral Sciences, University of California–Davis, School of Medicine, Sacramento, California, USA
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  • Randi J. Hagerman MD,

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

    Corresponding author
    1. Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California–Davis Medical Center, Sacramento, California, USA
    2. Department of Psychology, University of California–Davis, Davis, California, USA
    • Center for Mind and Brain, University of California–Davis, Davis, California, USA
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  • Funding agencies: This study is supported by NIH grants TL1DA024854 (to Jun Yi Wang), RL1AG032115, UL1 DE0199583, and HD036071 (to Randi J. Hagerman), and MH078041 and NS062412 (to Susan M. Rivera).

  • Relevant conflicts of interest/financial disclosures: Randi J. Hagerman has also received funding from Roche, Novartis, Seaside Therapeutics, Forest, Curemark, and the National Fragile X Foundation for treatment trials in fragile X syndrome and autism and has consulted with Novartis regarding treatment trials in those with fragile X syndrome.

Correspondence to: Susan M. Rivera, Center for Mind and Brain, 267 Cousteau Place, Davis, CA 95618, USA; srivera@ucdavis.edu

ABSTRACT

Approximately 40% of males with the fragile X premutation develop fragile X–associated tremor/ataxia syndrome after age 50. Although the thalamus and basal ganglia play a crucial role in movement disorders, their involvement in fragile X premutation carriers has not been systematically investigated. The current study characterized structural abnormalities associated with fragile X premutation carriers (with and without fragile X–associated tremor/ataxia syndrome) in the thalamus, caudate nucleus, putamen, and globus pallidus using T1-weighted and diffusion tensor imaging. Male premutation carriers with fragile X–associated tremor/ataxia syndrome showed significant volume atrophy and diffusion-weighted signal loss in all 4 structures compared with the control group. They also exhibited volume atrophy and diffusion-weighted signal loss in the thalamus and striatum compared with the premutation carriers without fragile X–associated tremor/ataxia syndrome. Importantly, many of the measurements exhibited robust correlations with symptom severity, with volume and diffusion-weighted imaging measurements displaying negative correlations and fractional anisotropy measurements displaying positive correlations. The current study demonstrated involvement of all 4 subcortical gray matter structures in fragile X–associated tremor/ataxia syndrome, with significant volume atrophy, and possible iron deposition indicated by the diffusion-weighted signal loss. The significant correlation between the subcortical measurements and symptom severity suggests the benefits of tracking structural changes in subcortical gray matter in future longitudinal studies for early detection and disease monitoring. © 2013 Movement Disorder Society

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