Brain Manganese Deposition in High Risk Neonates

描述（由申请人提供）：锰（Mn）是正常生长发育所必需的金属。过量的环境或饮食暴露会导致Mn沉积在Mn敏感的大脑区域，造成不良的心理和神经效应。需要肠外营养（PN）的患病婴儿可能面临更高的Mn神经毒性风险，因为新生儿PN溶液中含有高浓度的Mn， PN绕过正常的肠道吸收控制和胆道排泄机制，并且婴儿正处于大脑发育的关键阶段。此外，铁（Fe）缺乏症是患病新生儿的一个常见问题，它增加了Mn的脑摄取，因为Mn和Fe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新生儿的胎龄、铁状态、肝功能和膳食锰摄入量确定脑锰沉积过量风险增加的新生儿群体，并为适当的锰补充和接受PN的婴儿监测提出循证建议。本研究将通过磁共振（MR）成像研究40名接受锰补充PN治疗的新生儿和10名对照婴儿脑内顺磁元素Mn的沉积。两个特定目标将测试以下假设：(1)接受PN的新生儿选择性Mn敏感脑区MR T1和T2弛豫时间的缩短（Mn的标记）将与(a)饮食Mn摄入量，(b) PN天数，(c)血Mn水平（通过电感耦合血浆质谱测量）和(d)肝功能障碍/胆汁沉积（通过结合胆红素水平评估）直接相关。(2) T1和T2松弛时间的缩短与(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。婴儿脑锰积累增加的可能性以及与脑锰负担升高相关的潜在健康风险是暴露和易感性的关键、未探索的问题。膳食中Mn，特别是肠外给药的膳食Mn、胎龄、铁状态和肝功能障碍对新生儿大脑调节Mn沉积能力的影响尚未得到科学的解决。提出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的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.