Brain Manganese Deposition in High Risk Neonates

说明(申请人提供)：锰是正常生长和发育所必需的金属。过量的环境或饮食暴露会导致锰在对锰敏感的脑区沉积，造成不利的心理和神经影响。需要肠外营养(PN)的患病婴儿可能会面临更高的锰神经毒性风险，因为新生儿PN溶液中含有高浓度的锰，PN绕过了正常的肠道吸收控制和胆道对锰的排泄机制，而且婴儿正处于大脑发育的关键阶段。此外，缺铁(Fe)是患病新生儿中的一个常见问题，它会增加大脑对锰的摄取，因为锰和铁在中枢神经系统中竞争相同的载体运输系统。该项目的长期目标是根据胎龄、铁状况、肝功能和膳食锰摄入量确定脑内锰沉积过多的风险增加的新生儿人群，并为适当的锰补充和对接受PN的婴儿的监测提出循证建议。这项建议将通过磁共振(MR)成像研究接受补充锰的PN的40名新生儿和10名对照组婴儿的顺磁性元素锰的脑沉积。两个特定的目标将检验以下假设：(1)接受PN的新生儿对锰敏感的选择性脑区MR T1和T2松弛时间(一种标志)的缩短将与(A)饮食中的锰摄入量、(B)使用PN的天数、(C)血液中的锰水平(用电感耦合等离子体质谱测量)和(D)肝功能障碍/胆汁淤积(用结合胆红素水平评估)直接相关。(2)T1和T2松弛时间缩短与(A)胎龄和(B)铁状态(通过血清铁、铁蛋白、转铁蛋白、可溶性转铁蛋白受体和血红蛋白评估)呈负相关。婴儿脑内锰蓄积增加的可能性以及与脑锰负荷增加相关的潜在健康风险是暴露和易感性的关键、未被探索的问题。饮食中的锰，特别是非肠道摄入的饮食中的锰、胎龄、铁状态和肝功能障碍对新生儿大脑调节锰沉积的能力的影响尚未得到科学的解决。拟议的临床研究具有巨大的健康意义，并可能揭示长期肠外营养对婴儿和儿童神经功能障碍的发展和进展。

DESCRIPTION (provided by applicant): 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. The long term 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. 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 selective Mn-sensitive brain regions in neonates receiving PN will correlate directly with (a) dietary Mn intake, (b) days on PN, (c) blood Mn levels (measured by Inductively Coupled Plasma-Mass Spectrometry) and (d) hepatic dysfunction/cholestasis (assessed by conjugated bilirubin levels). (2) shortening of T1 and T2 relaxation times will correlate inversely with (a) gestational age and (b) 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.