title: Metabolomic analysis of CSF indicates brain metabolic impairment precedes hematological indices of anemia in the iron-deficient infant monkey.
abstract: OBJECTIVE
  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 using1H 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).
  
  
  CONCLUSIONS
  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.
authors: a Department of Pediatrics, Division of Neonatology , University of Minnesota , Minneapolis , USA.|b Center for Neurobehavioral Development , University of Minnesota , Minneapolis , USA.
authors: Raghavendra
authors: R
authors: Rao
authors: a Department of Pediatrics, Division of Neonatology , University of Minnesota , Minneapolis , USA.
authors: Kathleen
authors: K
authors: Ennis
authors: c Harlow Center for Biological Psychology , University of Wisconsin-Madison , USA.
authors: Gabriele R
authors: GR
authors: Lubach
authors: d Division of Biostatistics , School of Public Health, University of Minnesota , Minneapolis , USA.
authors: Eric F
authors: http://orcid.org/0000-0003-4663-2356
authors: EF
authors: Lock
authors: a Department of Pediatrics, Division of Neonatology , University of Minnesota , Minneapolis , USA.|b Center for Neurobehavioral Development , University of Minnesota , Minneapolis , USA.
authors: Michael K
authors: MK
authors: Georgieff
authors: c Harlow Center for Biological Psychology , University of Wisconsin-Madison , USA.
authors: Christopher L
authors: CL
authors: Coe
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000134:cerebrospinal fluid*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D004032:Diet; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004041:Dietary Fats / Q000008:administration & dosage; D004043:Dietary Fiber / Q000008:administration & dosage; D004044:Dietary Proteins / Q000008:administration & dosage; D005260:Female; D006454:Hemoglobins / Q000134:cerebrospinal fluid; D007501:Iron / Q000134:cerebrospinal fluid*; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics; D018977:Micronutrients / Q000008:administration & dosage / Q000134:cerebrospinal fluid; D011524:Protoporphyrins / Q000134:cerebrospinal fluid; D013048:Specimen Handling; D014168:Transferrin / Q000134:cerebrospinal fluid
chemical_list: D004040:Dietary Carbohydrates; D004041:Dietary Fats; D004043:Dietary Fiber; D004044:Dietary Proteins; D006454:Hemoglobins; D018977:Micronutrients; D011524:Protoporphyrins; D014168:Transferrin; C017803:zinc protoporphyrin; D007501:Iron
keywords: Cerebrospinal fluid; Energy metabolism; Infant; Iron; Iron deficiency; Metabolomics; Neurodevelopment; Rhesus monkey