Metabolomic analysis of CSF indicates brain metabolic impairment precedes hematological indices of anemia in the iron-deficient infant monkey

Raghavendra Rao; Kathleen Ennis; Gabriele R. Lubach; Eric F. Lock; Michael K. Georgieff; Christopher L. Coe

doi:10.1080/1028415X.2016.1217119

Metabolomic analysis of CSF indicates brain metabolic impairment precedes hematological indices of anemia in the iron-deficient infant monkey

Raghavendra Rao, Kathleen Ennis, Gabriele R. Lubach, Eric F. Lock, Michael K. Georgieff, Christopher L. Coe

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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.

Original language	English (US)
Pages (from-to)	40-48
Number of pages	9
Journal	Nutritional Neuroscience
Volume	21
Issue number	1
DOIs	https://doi.org/10.1080/1028415X.2016.1217119
State	Published - Jan 2 2018

Bibliographical note

Funding Information:
Funding This work was supported by the Eunice Kennedy Shriver National Institutes of Child Health and Human Development under grant numbers HD057064, HD080201, and HD039386. Funding for NMR instrumentation at University of Minnesota was provided by the Office of the Vice President for Research, the University of Minnesota Medical School, College of Biological Science, National Institutes of Health, National Science Foundation, and the Minnesota Medical Foundation.

Funding Information:
The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results within the paper, and Gulin Oz, PhD, for helpful comments on the manuscript.

Publisher Copyright:
© 2016 Informa UK Limited, trading as Taylor & Francis Group.

Keywords

Cerebrospinal fluid
Energy metabolism
Infant
Iron
Iron deficiency
Metabolomics
Neurodevelopment
Rhesus monkey

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10.1080/1028415X.2016.1217119

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944323

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title = "Metabolomic analysis of CSF indicates brain metabolic impairment precedes hematological indices of anemia in the iron-deficient infant monkey",

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.",

keywords = "Cerebrospinal fluid, Energy metabolism, Infant, Iron, Iron deficiency, Metabolomics, Neurodevelopment, Rhesus monkey",

author = "Raghavendra Rao and Kathleen Ennis and Lubach, {Gabriele R.} and Lock, {Eric F.} and Georgieff, {Michael K.} and Coe, {Christopher L.}",

note = "Funding Information: Funding This work was supported by the Eunice Kennedy Shriver National Institutes of Child Health and Human Development under grant numbers HD057064, HD080201, and HD039386. Funding for NMR instrumentation at University of Minnesota was provided by the Office of the Vice President for Research, the University of Minnesota Medical School, College of Biological Science, National Institutes of Health, National Science Foundation, and the Minnesota Medical Foundation. Funding Information: The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results within the paper, and Gulin Oz, PhD, for helpful comments on the manuscript. Publisher Copyright: {\textcopyright} 2016 Informa UK Limited, trading as Taylor & Francis Group.",

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AU - Ennis, Kathleen

AU - Lubach, Gabriele R.

AU - Lock, Eric F.

AU - Georgieff, Michael K.

AU - Coe, Christopher L.

N1 - Funding Information: Funding This work was supported by the Eunice Kennedy Shriver National Institutes of Child Health and Human Development under grant numbers HD057064, HD080201, and HD039386. Funding for NMR instrumentation at University of Minnesota was provided by the Office of the Vice President for Research, the University of Minnesota Medical School, College of Biological Science, National Institutes of Health, National Science Foundation, and the Minnesota Medical Foundation. Funding Information: The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results within the paper, and Gulin Oz, PhD, for helpful comments on the manuscript. Publisher Copyright: © 2016 Informa UK Limited, trading as Taylor & Francis Group.

PY - 2018/1/2

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N2 - 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.

AB - 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.

KW - Cerebrospinal fluid

KW - Energy metabolism

KW - Infant

KW - Iron

KW - Iron deficiency

KW - Metabolomics

KW - Neurodevelopment

KW - Rhesus monkey

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Metabolomic analysis of CSF indicates brain metabolic impairment precedes hematological indices of anemia in the iron-deficient infant monkey

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Keywords

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