Title: Metabolomic analysis of CSF indicates brain metabolic impairment precedes hematological indices of anemia in the iron-deficient infant monkey.
Legend: NMR spectra with typical metabolite peaks in the cerebrospinal fluid of one iron-sufficient (IS) and one iron-deficient (ID) rhesus monkey. Differences in citrate (cit), glutamine (gin), and pyruvate (pyr) indicate that brain energetics are affected by iron deficiency, and highlight the importance of iron supplementation if a developing infant becomes anemic.
Citation: Rao R, Ennis K, Lubach GR, Lock EF, Georgieff MK, Coe CL. (2016) Metabolomic analysis of CSF indicates brain metabolic impairment precedes hematological indices of anemia in the iron-deficient infant monkey. Nutritional Neuroscience. http://dx.doi.org/10.1080/1028415X.2016.1217119
Abstract: 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 1H NMR spectroscopy at 16.4 T 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 < 110 g/L and MCV < 60 fL) 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.
About the investigator: The Coe Lab’s research program concerns the relationship between asymmetrical activation patterns of the cerebral cortex and the immune system. These immune studies have been conducted in both healthy human subjects, as well as individuals who experienced unilateral hemispheric damage in the perinatal period or young adulthood. Persistent alterations in the physiological set points for certain immune responses have been found.