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

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.