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Neurometabolite Mapping Highlights Elevated Myo-inositol Profiles within the Developing Brain in Down Syndrome

View ORCID ProfilePrachi A. Patkee, View ORCID ProfileAna A. Baburamani, View ORCID ProfileKatherine R. Long, View ORCID ProfileRalica Dimitrova, View ORCID ProfileJudit Ciarrusta, Joanna Allsop, View ORCID ProfileEmer Hughes, View ORCID ProfileJohanna Kangas, View ORCID ProfileGrainne McAlonan, View ORCID ProfileMary A. Rutherford
doi: https://doi.org/10.1101/2020.07.20.211805
Prachi A. Patkee
1Centre for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King’s College London, St. Thomas’ Hospital, London, SE1 7EH, UK
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Ana A. Baburamani
1Centre for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King’s College London, St. Thomas’ Hospital, London, SE1 7EH, UK
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Katherine R. Long
2Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, SE1 1UL, UK
3MRC Centre for Neurodevelopmental Disorders, King’s College London, SE1 1UL, UK
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Ralica Dimitrova
1Centre for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King’s College London, St. Thomas’ Hospital, London, SE1 7EH, UK
4Department of Forensic and Neurodevelopmental Science, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, SE5 8AB, UK
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Judit Ciarrusta
1Centre for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King’s College London, St. Thomas’ Hospital, London, SE1 7EH, UK
4Department of Forensic and Neurodevelopmental Science, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, SE5 8AB, UK
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Joanna Allsop
1Centre for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King’s College London, St. Thomas’ Hospital, London, SE1 7EH, UK
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Emer Hughes
1Centre for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King’s College London, St. Thomas’ Hospital, London, SE1 7EH, UK
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Johanna Kangas
4Department of Forensic and Neurodevelopmental Science, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, SE5 8AB, UK
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Grainne McAlonan
4Department of Forensic and Neurodevelopmental Science, Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, SE5 8AB, UK
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Mary A. Rutherford
1Centre for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King’s College London, St. Thomas’ Hospital, London, SE1 7EH, UK
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  • For correspondence: prachi.patkee@kcl.ac.uk
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Abstract

The neurodevelopmental phenotype in Down Syndrome (DS), or Trisomy 21, is variable including a wide spectrum of cognitive impairment and a high risk of early-onset Alzheimer’s disease (AD). A key metabolite of interest within the brain in DS is Myo-inositol (Myo-ins). The NA+/Myo-ins co-transporter, is located on human chromosome 21 and is overexpressed in DS. In adults with DS, elevated brain Myo-ins has previously been associated with cognitive impairment and proposed as a risk marker for progression to AD. However, it is unknown if brain Myo-ins is increased earlier in development.

The aim of this study was to assess Myo-ins and key brain metabolites [N-acetylaspartate (NAA), Choline (Cho) and Creatine(Cr)] in the developing brain in DS and aged-matched controls. To achieve this we used mass spectrometry in early (10-20 weeks post conception) ex vivo fetal brain tissue samples from DS (n=14) and control (n=30) cases; and in vivo magnetic resonance spectroscopy (MRS) in neonates with DS (n=18) and aged matched controls (n= 25) scanned just after birth (36-45 weeks postmenstrual age.

We observed elevated Myo-ins in the ex vivo fetal cortical brain tissue in DS compared with controls. Relative to reference metabolites Cho and Cr, we also detected elevated ratios of Myo-ins and NAA in vivo in the basal ganglia and thalami, in neonates with DS, when compared to age-matched typically developing controls. Thus, a higher level of brain Myo-ins was evident as early as 10 weeks post conception and was measurable in vivo from 36 weeks post-menstrual age. Future work will determine if this early difference in metabolites is linked to cognitive outcomes in childhood or has utility as a potential treatment biomarker for early intervention.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 20, 2020.
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Neurometabolite Mapping Highlights Elevated Myo-inositol Profiles within the Developing Brain in Down Syndrome
Prachi A. Patkee, Ana A. Baburamani, Katherine R. Long, Ralica Dimitrova, Judit Ciarrusta, Joanna Allsop, Emer Hughes, Johanna Kangas, Grainne McAlonan, Mary A. Rutherford
bioRxiv 2020.07.20.211805; doi: https://doi.org/10.1101/2020.07.20.211805
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Neurometabolite Mapping Highlights Elevated Myo-inositol Profiles within the Developing Brain in Down Syndrome
Prachi A. Patkee, Ana A. Baburamani, Katherine R. Long, Ralica Dimitrova, Judit Ciarrusta, Joanna Allsop, Emer Hughes, Johanna Kangas, Grainne McAlonan, Mary A. Rutherford
bioRxiv 2020.07.20.211805; doi: https://doi.org/10.1101/2020.07.20.211805

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