Journal
NUTRITIONAL NEUROSCIENCE
Volume 21, Issue 1, Pages 40-48Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/1028415X.2016.1217119
Keywords
Cerebrospinal fluid; Energy metabolism; Infant; Iron; Iron deficiency; Metabolomics; Neurodevelopment; Rhesus monkey
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Funding
- Eunice Kennedy Shriver National Institutes of Child Health and Human Development [HD057064, HD080201, HD039386]
- Office of the Vice President for Research
- University of Minnesota Medical School
- College of Biological Science
- National Institutes of Health
- National Science Foundation
- Minnesota Medical Foundation
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Objectives: Iron deficiency (ID) anemia leads to long-term neurodevelopmental deficits by altering iron-dependent brain metabolism. The objective of the study was to determine if ID induces metabolomic abnormalities in the cerebrospinal fluid (CSF) in the pre-anemic stage and to ascertain the aspects of abnormal brain metabolism affected. Methods: Standard hematological parameters [hemoglobin (Hgb), mean corpuscular volume (MCV), transferrin (Tf) saturation, and zinc protoporphyrin/heme (ZnPP/H)] were compared at 2, 4, 6, 8, and 12 months in iron-sufficient (IS; n=7) and iron-deficient (ID; n=7) infant rhesus monkeys. Five CSF metabolite ratios were determined at 4, 8, and 12 months using H-1 NMR spectroscopy at 16.4T and compared between groups and in relation to hematologic parameters. Results: ID infants developed ID (Tf saturation <25%) by 4 months of age and all became anemic (Hgb < 110g/L and MCV < 60fL) at 6 months. Their heme indices normalized by 12 months. Pyruvate/glutamine and phosphocreatine/creatine (PCr/Cr) ratios in CSF were lower in the ID infants by 4 months (P < 0.05). The PCr/Cr ratio remained lower at 8 months (P = 0.02). ZnPP/H, an established blood marker of pre-anemic ID, was positively correlated with the CSF citrate/glutamine ratio (marginal correlation, 0.34; P < 0.001; family wise error rate = 0.001). Discussion: Metabolomic analysis of the CSF is sensitive for detecting the effects of pre-anemic ID on brain energy metabolism. Persistence of a lower PCr/Cr ratio at 8 months, even as hematological measures demonstrated recovery from anemia, indicate that the restoration of brain energy metabolism is delayed. Metabolomic platforms offer a useful tool for early detection of the impact of ID on brain metabolism in infants.
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