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Phenotypes of hypofrontality in older female fragile X premutation carriers

Authors

  • Jin-Chen Yang PhD,

    Corresponding author
    1. Department of Neurology, University of California, Davis, Sacramento, CA
    • Center for Mind and Brain, University of California, Davis, Davis, CA
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  • Christa Simon BS,

    1. Center for Mind and Brain, University of California, Davis, Davis, CA
    2. Department of Neurology, University of California, Davis, Sacramento, CA
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  • Yu-Qiong Niu PhD,

    1. Center for Mind and Brain, University of California, Davis, Davis, CA
    2. Department of Neurology, University of California, Davis, Sacramento, CA
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  • Mark Bogost BS,

    1. Center for Mind and Brain, University of California, Davis, Davis, CA
    2. Department of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, CA
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  • Andrea Schneider PhD,

    1. Center for Mind and Brain, University of California, Davis, Davis, CA
    2. Medical Investigations of Neurodevelopmental Disorders Institute, University of California, Davis, Sacramento, CA
    3. Department of Pediatrics, School of Medicine, University of California, Davis, Sacramento, CA
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  • Flora Tassone PhD,

    1. Medical Investigations of Neurodevelopmental Disorders Institute, University of California, Davis, Sacramento, CA
    2. Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA
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  • Andreea Seritan MD,

    1. Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, CA
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  • Jim Grigsby PhD,

    1. Departments of Medicine and Psychology, University of Colorado Denver, Denver, CO
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  • Paul J. Hagerman MD, PhD,

    1. Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA
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  • Randi J. Hagerman MD,

    1. Medical Investigations of Neurodevelopmental Disorders Institute, University of California, Davis, Sacramento, CA
    2. Department of Pediatrics, School of Medicine, University of California, Davis, Sacramento, CA
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  • John M. Olichney MD

    Corresponding author
    1. Department of Neurology, University of California, Davis, Sacramento, CA
    • Center for Mind and Brain, University of California, Davis, Davis, CA
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Address correspondence to Dr Olichney or Dr Yang, University of California, Davis, School of Medicine, Center for Mind and Brain, 267 Cousteau Place, Davis, CA 95618-5412. E-mail: jmolichney@ucdavis.edu or jchyang@ucdavis.edu

Abstract

Objective

To investigate the nature of cognitive impairments and underlying brain mechanisms in older female fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome (FXTAS).

Methods

Extensive neuropsychological testing and cognitive event-related brain potentials (ERPs; particularly, the auditory P300) were examined in 84 female participants: 33 fragile X premutation carriers with FXTAS (mean age = 62.8 years), 25 premutation carriers without FXTAS (mean age = 55.4 years), and 26 normal healthy controls (mean age = 59.3 years).

Results

Both premutation groups exhibited executive dysfunction on the Behavioral Dyscontrol Scale, with subtle impairments in inhibition and performance monitoring in female carriers without FXTAS, and more substantial deficits in FXTAS women. However, the female carrier group without FXTAS showed more pronounced deficiencies in working memory. Abnormal ERPs were recorded over the frontal lobes, where FXTAS patients showed both P300 amplitude reduction and latency prolongation, whereas only decreased frontal P300 amplitudes were found in carriers without FXTAS. These frontal P300 measures correlated with executive function and information processing speed.

Interpretation

The neuropsychological testing and ERP results of the present study provide support for the hypothesis that executive dysfunction is the primary cognitive impairment among older female premutation carriers both with and without FXTAS, although these deficits are relatively mild compared to those in FXTAS males. These findings are consistent with a synergistic effect of the premutation and aging on cognitive impairment among older female fragile X premutation carriers, even in those without FXTAS symptoms. Ann Neurol 2013;74:275–283

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