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 M Mcalonan,Mary A Rutherford,Enrico De Vita

doi:10.1016/j.nbd.2021.105316

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 (mIns). The NA+/mIns co-transporter is located on human chromosome 21 and is overexpressed in DS. In adults with DS, elevated brain mIns was previously associated with cognitive impairment and proposed as a risk marker for progression to AD. However, it is unknown if brain mIns is increased earlier in development.The aim of this study was to estimate mIns concentration levels and key brain metabolites [N-acetylaspartate (NAA), Choline (Cho) and Creatine (Cr)] in the developing brain in DS and aged-matched controls. We used in vivo magnetic resonance spectroscopy (MRS) in neonates with DS (n = 12) and age-matched controls (n = 26) scanned just after birth (36–45 weeks postmenstrual age). Moreover, 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.Relative to [Cho] and [Cr], we report elevated ratios of [mIns] in vivo in the basal ganglia/thalamus, in neonates with DS, when compared to age-matched typically developing controls. Glycine concentration ratios [Gly]/[Cr] and [Cho]/[Cr] also appear elevated. We observed elevated [mIns] in the ex vivo fetal cortical brain tissue in DS compared with controls.In conclusion, a higher level of brain mIns 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.

Highlights

Down Syndrome (DS) is a complex genetic condition, resulting from the triplication of human chromosome 21 (HSA21; (Trisomy 21), and is associated with a wide spectrum of neurodevelopmental outcomes (Karmiloff-Smith et al, 2016; Baburamani et al, 2019)
We found a statistically significant elevation in total Myo-inositol in DS fetal brains compared to controls (p < 0.05, d = -0.7), when controlled for age (Figure 4C)
We found that absolute Myo-ins was elevated in fetal brain tissue in DS, prior to 20 weeks when compared to controls, markedly so earlier in gestation at 10 weeks

Summary

Introduction

Down Syndrome (DS) is a complex genetic condition, resulting from the triplication of human chromosome 21 (HSA21; (Trisomy 21), and is associated with a wide spectrum of neurodevelopmental outcomes (Karmiloff-Smith et al, 2016; Baburamani et al, 2019). Higher levels of Myo-ins have been found to correlate with poor cognitive performance, suggesting that this metabolite might have utility for monitoring response to treatment and/or constitute a treatment target (Lin et al, 2016) Consistent with the latter, studies in mouse models of DS have shown that higher levels of Myo-ins could be reduced by treatment with lithium, which rescued both synaptic plasticity and memory deficits (Huang et al, 1999; Contestabile et al, 2013). Whilst such studies have made valuable first steps to revealing a link between the metabolite profile of DS and functional outcomes, it is unknown when this alteration in Myo-ins (and/or other metabolites supporting brain function) emerges

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