Brain Manganese Deposition in High Risk Neonates
Condition: Necrotizing Enterocolitis; Digestive System Abnormalities; Cholestasis
MeSH terms: Enterocolitis; Cholestasis; Enterocolitis, Necrotizing; Digestive System Abnormalities
Study type: Observational

Summary: 
      Excessive exposure to manganese (Mn) results in Mn deposition in the brain causing adverse
      neurological effects. Sick infants requiring parenteral nutrition (PN) may be at increased
      risk of Mn neurotoxicity because neonatal PN solutions contain high concentrations of Mn.
      This proposal will investigate brain deposition of Mn, a paramagnetic element, by magnetic
      resonance (MR) imaging in preterm and term neonates receiving Mn-supplemented PN and
      gestational age-matched control infants. The goals of this project are to identify neonatal
      populations that are at increased risk of excessive brain Mn deposition based on their
      gestational age, iron status, hepatic function and dietary Mn intake, and to make
      evidence-based recommendations for appropriate Mn supplementation and monitoring of infants
      receiving PN.
    

Detailed description: 
      Manganese (Mn) is an essential metal needed for normal growth and development. Excessive
      environmental or dietary exposure results in Mn deposition in Mn-sensitive brain regions
      causing adverse psychological and neurological effects. Sick infants requiring parenteral
      nutrition (PN) may be at increased risk of Mn neurotoxicity because neonatal PN solutions
      contain high concentrations of Mn, PN bypasses the normal intestinal absorptive control and
      biliary excretory mechanisms for Mn, and infants are at a critical stage of brain
      development. Furthermore, iron (Fe) deficiency, a common problem among sick neonates,
      increases Mn brain uptake because Mn and Fe compete for the same carrier transport systems in
      the central nervous system. This proposal will investigate brain deposition of Mn, a
      paramagnetic element, by magnetic resonance (MR) imaging in 40 neonates receiving
      Mn-supplemented PN and 10 control infants.

      Two specific aims will test the following hypotheses:

        1. Shortening of MR T1 and T2 relaxation times (a marker for Mn) in Mn-sensitive brain
           regions in neonates receiving PN will correlate directly with

             -  dietary Mn intake,

             -  days on PN,

             -  blood Mn levels (measured by Inductively Coupled Plasma-Mass Spectrometry)

             -  hepatic dysfunction/cholestasis (assessed by conjugated bilirubin levels).

        2. shortening of T1 and T2 relaxation times will correlate inversely with

             -  gestational age

             -  Fe status (assessed by serum Fe, ferritin, transferrin, soluble transferrin
                receptor and hemoglobin).

      The potential for increased brain Mn accumulation in infants and the potential health risks
      associated with elevated brain Mn burden represent crucial, unexplored issues of exposure and
      susceptibility. The impact of dietary Mn, and especially parenterally delivered dietary Mn,
      gestational age, Fe status, and hepatic dysfunction on the ability of the neonatal brain to
      regulate Mn deposition has not been scientifically addressed. The proposed clinical
      investigation has enormous health significance and may shed light on the development and
      progression of neurological dysfunction in infants and children on prolonged parenteral
      nutrition.
    

Intervention name(s): remove Mn from PN if evidence of increased brain Mn on MRI
Intervention type(s): Dietary Supplement
Intervention description(s): trace element cocktail will be withheld and zinc, copper and chromium added to PN individually.
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Neonates in the NICU on prolonged PN
      
Biospecimen description: 
      Blood
    
Keywords: Manganese; Neonatal Intensive Care; MRI; Parenteral Nutrition; Prematurity