Age-related differences in neurometabolite concentrations during early infancy: A cross-sectional analysis of the HBCD Release 1.0

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Abstract Background Developmental trajectories of low-concentration neurometabolites such as the neurotransmitter γ-aminobutyric acid (GABA), and the antioxidants glutathione (GSH) and ascorbate (Asc) across early infancy remain unexplored. Advances in spectral editing enabled the measurement of these key molecules together with high-concentration metabolites like N-acetylaspartate (NAA) and glutamate (Glu) in the HEALthy Brain and Child Development (HBCD) study, the largest longitudinal study of early brain development in the United States. Purpose To determine the age-associated trajectories of 14 key neurometabolites during early infancy from a cross-sectional 1 H-MRS dataset. Materials and Methods HBCD utilizes ISTHMUS, an integrated MRS sequence that includes both an unedited short-echo-time PRESS acquisition and an advanced 4-step Hadamard-encoded sequence, HERCULES to enable measurement of both high- and low-concentration metabolites. Metabolite quantification was carried out by the HBCD Data Coordinating Center (HDCC) using an automated Osprey pipeline, with data from 201 infants ages 0 – 10 weeks adjusted age included in the tabular imaging results in HBCD data release 1.0. After excluding preterm born infants and data with poor linewidth or model quality metric, we tested for linear associations with adjusted age for each metabolite. Results Concentration estimates of total NAA (tNAA), total creatine (tCr) and glutamate (Glu) as well as the combined sum of glutamate and glutamine (Glx) significantly increased across ages 0 – 10 weeks, while myo-inositol (mI) decreased. GABA and GSH showed age-related trends, but did not reach significance. Levels of the lipid precursor phosphorylethanolamine (PE) and Asc are higher in the first months than established adult values. Conclusion Multiple metabolites showed significant age-related changes during early infancy. While GABA and GSH did not, future work will establish whether the trends suggested here contribute to linear or non-linear patterns across the first years of life. Summary Statement HBCD MRS Data Release 1.0 cross-sectional analysis of tabulated results shows significant changes of neurometabolite levels in the thalamus from birth to 10-week-old infants. Key Results This study provides the first ever concentration level reports of multiple low-concentration metabolites such as GABA+, GSH, PE, Lac, Asc as well as their cross-sectional trajectory in early postnatal period of brain development.

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