Non-invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1

Authors

  • Uzay E. Emir,

    1. Department of Radiology, Medical School, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota, USA
    Current affiliation:
    1. Oxford Centre for Functional MRI of the Brain (FMRIB), John Radcliffe Hospital, University of Oxford, Headington, Oxford, UK
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  • Howard Brent Clark,

    1. Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota, USA
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  • Manda L. Vollmers,

    1. Department of Radiology, Medical School, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota, USA
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  • Lynn E. Eberly,

    1. Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA
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  • Gülin Öz

    Corresponding author
    1. Department of Radiology, Medical School, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota, USA
    • Address correspondence and reprint requests to Gülin Öz, Center for MR Research, 2021 6th St. S.E., Minneapolis, MN 55455, USA. E-mail: gulin@cmrr.umn.edu

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is a hereditary, progressive and fatal movement disorder that primarily affects the cerebellum. Non-invasive imaging markers to detect early disease in SCA1 will facilitate testing and implementation of potential therapies. We have previously demonstrated the sensitivity of neurochemical levels measured by 1H magnetic resonance spectroscopy (MRS) to progressive neurodegeneration using a transgenic mouse model of SCA1. In order to investigate very early neurochemical changes related to neurodegeneration, here we utilized a knock-in mouse model, the Sca1154Q/2Q line, which displays milder cerebellar pathology than the transgenic model. We measured cerebellar neurochemical profiles of Sca1154Q/2Q mice and wild-type littermates using 9.4T MRS at ages 6, 12, 24, and 39 weeks and assessed the cerebellar pathology of a subset of the mice at each time point. The Sca1154Q/2Q mice displayed very mild cerebellar pathology even at 39 weeks, however, were distinguished from wild types by MRS starting at 6 weeks. Taurine and total choline levels were significantly lower at all ages and glutamine and total creatine levels were higher starting at 12 weeks in Sca1154Q/2Q mice than controls, demonstrating the sensitivity of neurochemical levels to neurodegeneration related changes in the absence of overt pathology.

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We measured cerebellar neurochemical alterations in a knock-in mouse model of spinocerebellar ataxia type 1, a hereditary movement disorder, using ultra-high field magnetic resonance spectroscopy (MRS). Very early neurochemical alterations were detectable prior to overt pathology in the volume-of-interest for MRS. Alterations were indicative of osmolytic changes and of disturbances in membrane phospholipid and energy metabolism.

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