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

Patkee, P. A.; Baburamani, A. A.; Long, K.; Dimitrova, R. V.; Ciarrusta, J.; Allsop, J.; Hughes, E.; Kangas, J.; McAlonan, G.; Rutherford, M.

doi:10.1101/2020.07.20.211805

bioRxiv · 10.1101/2020.07.20.211805

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

Patkee, P. A.·Baburamani, A. A.·Long, K.·Dimitrova, R. V.·Ciarrusta, J.·Allsop, J.·Hughes, E.·Kangas, J.·McAlonan, G.·Rutherford, M.

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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 Alzheimers 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.

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Patkee, P. A., Baburamani, A. A., Long, K., Dimitrova, R. V., Ciarrusta, J., Allsop, J., Hughes, E., Kangas, J., McAlonan, G., Rutherford, M.. 2020-07-20. Neurometabolite Mapping Highlights Elevated Myo-inositol Profiles within the Developing Brain in Down Syndrome. https://doi.org/10.1101/2020.07.20.211805

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