title: Neuroimaging identifies increased manganese deposition in infants receiving parenteral nutrition.
abstract: BACKGROUND
  Manganese, an essential metal for normal growth and development, is neurotoxic on excessive exposure. Standard trace element-supplemented neonatal parenteral nutrition (PN) has a high manganese content and bypasses normal gastrointestinal absorptive control mechanisms, which places infants at risk of manganese neurotoxicity. Magnetic resonance (MR) relaxometry demonstrating short T1 relaxation time (T1R) in the basal ganglia reflects excessive brain manganese accumulation.
  
  
  OBJECTIVE
  This study tested the hypothesis that infants with greater parenteral manganese exposure have higher brain manganese accumulation, as measured by MR imaging, than do infants with lower parenteral manganese exposure.
  
  
  METHODS
  Infants exposed to parenteral manganese were enrolled in a prospective cohort study. Infants classified as having high manganese exposure received >75% of their nutrition in the preceding 4 wk as PN. All others were classified as having low exposure. Daily parenteral and enteral manganese intakes were calculated. Whole-blood manganese was measured by high-resolution inductively coupled plasma mass spectrometry. Brain MR relaxometry was interpreted by a masked reviewer. Linear regression models, adjusted for gestational age (GA) at birth, estimated the association of relaxometry indexes with total and parenteral manganese exposures.
  
  
  RESULTS
  Seventy-three infants were enrolled. High-quality MR images were available for 58 infants, 39 with high and 19 with low manganese exposure. Four infants with a high exposure had blood manganese concentrations >30 μg/L. After controlling for GA, higher parenteral and total manganese intakes were associated with a lower T1R (P = 0.01) in the globus pallidus and putamen but were not associated with whole-blood manganese (range: 3.6-56.6 μg/L). Elevated conjugated bilirubin magnified the association between parenteral manganese and decreasing T1R.
  
  
  CONCLUSIONS
  A short T1R for GA identifies infants at risk of increased brain manganese deposition associated with PN solutions commonly used to nourish critically ill infants. These trials were registered at clinicaltrials.gov as NCT00392977 and NCT00392730.
authors.affiliation: Departments of Pediatrics, Center for Molecular Toxicology, and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN; Departments of Pediatrics and Obstetrics and Gynecology and Woman's Health, Albert Einstein College of Medicine of Montefiore Health and The Children's Hospital at Montefiore, Bronx, NY; judy.aschner@einstein.yu.edu.
authors.forename: Judy L
authors.identifier: http://orcid.org/0000-0001-8420-7794
authors.initials: JL
authors.lastname: Aschner
authors.affiliation: Vanderbilt Center for Imaging Sciences.
authors.forename: Adam
authors.initials: A
authors.lastname: Anderson
authors.affiliation: Biostatistics, and.
authors.forename: James Christopher
authors.initials: JC
authors.lastname: Slaughter
authors.affiliation: Center for Molecular Toxicology, and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN;
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.affiliation: Departments of Pediatrics.
authors.forename: Steven
authors.initials: S
authors.lastname: Steele
authors.affiliation: Departments of Pediatrics.
authors.forename: Amy
authors.initials: A
authors.lastname: Beller
authors.affiliation: Departments of Pediatrics.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mouvery
authors.affiliation: Department of Pediatrics, Wake Forest Baptist Health, Winston-Salem, NC; and.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Furlong
authors.affiliation: Departments of Pediatrics, Physical Medicine and Rehabilitation, Center for Molecular Toxicology, and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN; Department of Pediatrics and the Research Institute at Nationwide Children's Hospital, Columbus, OH.
authors.forename: Nathalie L
authors.initials: NL
authors.lastname: Maitre
mesh_terms: D001479:Basal Ganglia / Q000378:metabolism*; D001663:Bilirubin / Q000031:analogs & derivatives / Q000097:blood; D002657:Child Development; D015331:Cohort Studies; D005260:Female; D005917:Globus Pallidus / Q000378:metabolism; D006776:Hospitals, Pediatric; D006785:Hospitals, University; D006801:Humans; D007223:Infant; D007227:Infant Nutritional Physiological Phenomena; D007363:Intensive Care Units, Neonatal; D008279:Magnetic Resonance Imaging; D008297:Male; D008345:Manganese / Q000097:blood / Q000378:metabolism*; D020149:Manganese Poisoning / Q000097:blood / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D059906:Neuroimaging; D009474:Neurons / Q000378:metabolism*; D010288:Parenteral Nutrition / Q000009:adverse effects*; D010865:Pilot Projects; D011446:Prospective Studies; D011699:Putamen / Q000378:metabolism
chemical_list: C016266:bilirubin glucuronate; D008345:Manganese; D001663:Bilirubin
keywords: infants; manganese; neuroimaging; parenteral nutrition; trace metals