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Cerebellar neurochemical alterations in spinocerebellar ataxia type 14 appear to include glutathione deficiency

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Abstract

Autosomal dominant ataxia type 14 (SCA14) is a rare usually adult-onset progressive disorder with cerebellar neurodegeneration caused by mutations in protein kinase C gamma. We set out to examine cerebellar and extracerebellar neurochemical changes in SCA14 by MR spectroscopy. In 13 SCA14 patients and 13 healthy sex- and age-matched controls, 3-T single-voxel brain proton MR spectroscopy was performed in a cerebellar voxel of interest (VOI) at TE = 30 ms to obtain a neurochemical profile of metabolites with short relaxation times. In the cerebellum and in additional VOIs in the prefrontal cortex, motor cortex, and somatosensory cortex, a second measurement was performed at TE = 144 ms to mainly extract the total N-acetyl-aspartate (tNAA) signal besides the signals for total creatine (tCr) and total choline (tCho). The cerebellar neurochemical profile revealed a decrease in glutathione (6.12E−06 ± 2.50E−06 versus 8.91E−06 ± 3.03E−06; p = 0028) and tNAA (3.78E−05 ± 5.67E−06 versus 4.25E−05 ± 5.15E−06; p = 0023) and a trend for reduced glutamate (2.63E−05 ± 6.48E−06 versus 3.15E−05 ± 7.61E−06; p = 0062) in SCA14 compared to controls. In the tNAA-focused measurement, cerebellar tNAA (296.6 ± 42.6 versus 351.7 ± 16.5; p = 0004) and tCr (272.1 ± 25.2 versus 303.2 ± 31.4; p = 0004) were reduced, while the prefrontal, somatosensory and motor cortex remained unaffected compared to controls. Neuronal pathology in SCA14 detected by MR spectroscopy was restricted to the cerebellum and did not comprise cortical regions. In the cerebellum, we found in addition to signs of neurodegeneration a glutathione reduction, which has been associated with cellular damage by oxidative stress in other neurodegenerative diseases such as Parkinson’s disease and Friedreich’s ataxia.

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Abbreviations

CHESS:

Chemical shift selective suppression

tCho:

Total choline

tCr:

Total creatine

Glu:

Glutamate

Gln:

Glutamine

GSH:

Glutathione

Glx:

The combined value of glutamate and glutamine

HC:

Healthy controls

Ins:

Inositol

Lac:

Lactate

tNAA:

N-Acetylaspartate

NAAG:

NAA-Glutamate

PRESS:

Point-resolved spectroscopy sequence

SCA14:

Spinocerebellar ataxia type 14

VOI:

Volume of interest

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Acknowledgments

We thank Susan Pikol and Cynthia Kraut for excellent technical support and Hanna Zimmermann, Ella Kadas, Timm Oberwahrenbrock, and Leonora Zange for supporting the study logistics.

Conflicts of interest

SD received financial support for travel and research projects from Teva and Actelion and speakers honoraria from Actelion, SD reports no specific conflict of interest. JLR reports no conflict of interest. TSH received travel grants from Allergan. AUB is cofounder and associate of Motognosis. He received consulting fees, speaker honoraria and research grants from Novartis, Biogen Idec, Teva Pharmaceuticals, Bayer, and Heidelberg Engineering. He reports no conflict of interest in regard to the current study. SP and SM report no conflict of interest. JW serves on advisory boards for Novartis and Biogen Idec. He received a research grant from Novartis, and speaker honoraria from Bayer, Novartis, Teva and Biogen Idec. He is supported by the German ministry of science (BMBF/KKNMS). ME has no direct conflict of interests concerning this manuscript. He has received grant support from AstraZeneca and Sanofi, has participated in advisory board meetings of Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Pfizer, Sanofi and has received honoraria from Astra Zeneca, Bayer, Berlin Chemie, Bristol-Myers Squibb, Boehringer-Ingelheim, Desitin, Eisei, Ever, Glaxo Smith Kline, MSD, Novartis, Pfizer, Sanofi, Takeda, Trommsdorff. TK receives/has received research support from the Deutsche Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Forschung (BMBF) and the European Union (EU). He has received a lecture honorarium from Lundbeck and from Biogen Idec. He receives/has received royalties for book publications from Thieme, Urban & Schwarzenberg, Kohlhammer, Elsevier, Wissenschaftliche Verlagsgesellschaft Stuttgart and M. Dekker. MM reports no conflict of interest. FP reports to have received grant support from Sanofi, Beyer, Pfizer, and Teva where he sees no direct conflict of interest with this work. FP is supported by the Deutsche Forschungsgemeinschaft (DFG Exc 257), the Bundesministerium für Bildung und Forschung (BMBF Competence Network Multiple Sclerosis), and the European Union (FP 7, combims.eu).

Ethical standard

The study was approved by the local ethics committee of the Charité - Universitätsmedizin Berlin and the University of Bonn and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants gave informed written consent.

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    Authors and Affiliations

    1. Department of Neurology, Charité, Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany

      Sarah Doss, Tanja Schmitz-Hübsch, Stephan Maul, Matthias Endres & Friedemann Paul

    2. Experimental and Clinical Research Center, Charité, Universitätsmedizin Berlin and Max-Delbrück Center for Molecular Medicine Berlin, Lindenberger Weg 80, 13125, Berlin, Germany

      Sarah Doss & Friedemann Paul

    3. Institute of Neuropathology, Charité, Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany

      Jan Leo Rinnenthal

    4. NeuroCure Clinical Research Center, Charité, Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany

      Alexander U. Brandt, Sebastian Papazoglou, Jens Würfel, Matthias Endres & Friedemann Paul

    5. Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Leo-Brandt-Str. 1, 52425, Jülich, Germany

      Silke Lux & Martina Minnerop

    6. Institute of Neuroradiology, Universitätsmedizin Goettingen, Robert-Koch-Str. 40, 37075, Goettingen, Germany

      Jens Würfel

    7. Centrum für Schlaganfallforschung Berlin, Charité, Universitätsmedizin Berlin, Berlin, Germany

      Matthias Endres

    8. Department of Neurology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

      Thomas Klockgether & Martina Minnerop

    9. German Centre for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany

      Thomas Klockgether

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    1. Sarah Doss
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    Correspondence to Sarah Doss.

    Additional information

    S. Doss, J. L. Rinnenthal, M. Minnerop, and F. Paul contributed equally.

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    Doss, S., Rinnenthal, J.L., Schmitz-Hübsch, T. et al. Cerebellar neurochemical alterations in spinocerebellar ataxia type 14 appear to include glutathione deficiency. J Neurol 262, 1927–1935 (2015). https://doi.org/10.1007/s00415-015-7788-2

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