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.

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.

Inclusion Criteria:

1. Greater than 30 days postnatal age
2. In the preceding four weeks have received >75% of their nutrition as Mn-supplemented PN
3. Clinically stable for transport to the MR facility
4. Signed parental consent.

Exclusion Criteria:

1. Any infant not expected to survive to the age of 3 months or
2. Not expected to achieve sufficient clinical stability to tolerate the MRI procedure.

Neonates in the NICU on prolonged PN