Brain metabolite alterations and cognitive dysfunction in early Huntington's disease§

Authors

  • Paul G. Unschuld MD,

    Corresponding author
    1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    • Department of Psychiatry and Behavioral Sciences, Division of Psychiatric Neuroimaging, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street/Phipps 300, Baltimore, MD 21287
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  • Richard A. E. Edden PhD,

    1. Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA
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  • Aaron Carass MSc,

    1. Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Xinyang Liu PhD,

    1. Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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  • Megan Shanahan MHS,

    1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Xin Wang PhD,

    1. Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Kenichi Oishi MD, PhD,

    1. Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Jason Brandt PhD,

    1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Susan S. Bassett PhD,

    1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Graham W. Redgrave MD,

    1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Russell L. Margolis MD,

    1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Peter C. M. van Zijl PhD,

    1. Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA
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  • Peter B. Barker PhD,

    1. Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA
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  • Christopher A. Ross MD, PhD

    1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    3. Department of Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Funding agencies: This study was made possible by grant support from The Johns Hopkins Brain Science Institute (BSi), NINDS NS16375, NIH-NCRR P41-RR015241, P50AG005146 and from NIH T32MH015330 (to P.G.U.).

  • Relevant conflicts of interest/financial disclosures: Equipment used in the study was manufactured by Philips. Peter C. M. van Zijl receives grant support from Philips, is a paid lecturer for Philips, and is the inventor of technology that is licensed to Philips. This arrangement has been approved by Johns Hopkins in accordance with its conflict of interest policies.

  • §

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

Abstract

Huntington's disease (HD) is a neurodegenerative disorder characterized by early cognitive decline that progresses at later stages to dementia and severe movement disorder. HD is caused by a cytosine–adenine–guanine triplet-repeat expansion mutation in the Huntingtin gene, allowing early diagnosis by genetic testing. This study aimed to identify the relationship of N-acetylaspartate and other brain metabolites to cognitive function in HD-mutation carriers by using high-field-strength magnetic resonance spectroscopy (MRS) at 7 Tesla. Twelve individuals with the HD mutation in premanifest or early-stage disease versus 12 healthy controls underwent 1H magnetic resonance spectroscopy (7.2 mL voxel in the posterior cingulate cortex) at 7 Tesla, and also T1-weighted structural magnetic resonance imaging. All participants received standardized tests of cognitive functioning including the Montreal Cognitive Assessment and standardized quantified neurological examination within an hour before scanning. Individuals with the HD mutation had significantly lower posterior cingulate cortex N-acetylaspartate (−9.6%, P = .02) and glutamate (−10.1%, P = .02) levels than did controls. In contrast, in this small group, measures of brain morphology including striatal and ventricle volumes did not differ significantly. Linear regression with Montreal Cognitive Assessment scores revealed significant correlations with N-acetylaspartate (r2 = 0.50, P = .01) and glutamate (NAA) (r2 = 0.64, P = .002) in HD subjects. Our data suggest a relationship between reduced N-acetylaspartate and glutamate levels in the posterior cingulate cortex with cognitive decline in the early stages of HD. N-acetylaspartate and glutamate magnetic resonance spectroscopy signals of the posterior cingulate cortex region may serve as potential biomarkers of disease progression or treatment outcome in HD and other neurodegenerative disorders with early cognitive dysfunction, when structural brain changes are still minor. © 2012 Movement Disorder Society

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