Choline Supplementation as a Neurodevelopmental Intervention in Fetal Alcohol Spectrum Disorders

 描述（由申请人提供）：已发表的数据表明，2-5%的美国人口患有胎儿酒精谱系障碍（FASD）-一组由产前酒精暴露引起的身体异常和神经发育缺陷（May & Gossage，2001）。尽管有深刻的公共卫生负担，但还没有临床试验试图直接解决FASD中如此衰弱的神经发育缺陷。广泛的临床前工作（托马斯等）提供了证据，证明在动物模型中补充胆碱可有效减轻产前酒精暴露引起的神经发育缺陷。我们的小组已经采取了初步措施，通过两项随机、双盲、安慰剂对照试验将这项工作转化为人类。我们首先进行了一项试点研究，以确保20名FASD儿童补充胆碱的可行性、耐受性和安全性（Fuglestad et al，2013）。接下来，我们完成了一项对另外40名参与者的研究，目的是为幼儿建立目标剂量，测试记忆领域的功效，并确定胆碱影响的发育窗口（详见“初步研究”）。 简单地说，我们的试点数据显示：1。患有FASD的儿童平均摄入的膳食胆碱不足; 2.补充胆碱对2-5奥尔兹安全、耐受、可行。与安慰剂相比，9个月的补充增加了儿童的外显记忆表现; 4.在2-3岁的奥尔兹中观察到显著的记忆改善，但在4-5奥尔兹中没有。对于2-3奥尔兹，胆碱组的记忆改善率为21个百分点，而安慰剂组为2个百分点; 5.剂量范围为10-19 mg/kg与记忆的最大改善相关; 6.一个非常常见的单核苷酸多态性（SNP）（rs 12325817），与内源性胆碱的产生有关，似乎可以调节胆碱对FASD儿童的疗效。 这些发现直接为下一项研究提供了信息。目的1涉及在60名2至5岁的FASD儿童中评估19 mg/kg的剂量。该给药方案将优化神经认知益处并进一步增强干预的耐受性。除了继续评估胆碱对记忆的益处外，目标2还增加了注意力和执行功能的测量作为可能的额外目标。增加了NIH Flanker抑制控制和注意力测试以及幼儿执行功能量表（在我们上次研究中进行了试点测试）。目标3增加了一个纵向组成部分-它将评估40名儿童在治疗后两年的时间内，以确定胆碱的影响的持久性。最后，目标4将进一步研究已知SNP在胆碱合成中作为观察到的治疗效果的调节剂的作用。 总之，拟议的研究将继续翻译胆碱的应用-从实验性临床前工作到FASD儿童神经发育缺陷的循证干预。

 DESCRIPTION (provided by applicant): Published data indicate that 2-5% of the U.S. population has Fetal Alcohol Spectrum Disorder (FASD) - a set of physical anomalies and neurodevelopmental deficits caused by prenatal alcohol exposure (May & Gossage, 2001). Despite the profound public health burden, there have been no clinical trials that have attempted to directly address the neurodevelopmental deficits that are so debilitating in FASD. Extensive pre- clinical work (Thomas et al. and others) has provided evidence that choline supplementation is effective in attenuating the neurodevelopmental deficits caused by prenatal alcohol exposure in animal models. Our group has taken the initial steps toward translating this work to humans with two randomized, double-blind, placebo- controlled trials. We first conducted a pilot study to ensure the feasibility, tolerability, and safety of choline supplementation in 20 children with FASD (Fuglestad et al, 2013). Next, we completed a study of 40 additional participants with the goals of establishing a target dosage for young children, testing efficacy in the domain of memory, and determining a developmental window for choline's effects (detailed in `preliminary studies'). Briefly, our pilot data revealed that: 1. Children wih FASD consume insufficient dietary choline on average; 2. Choline supplementation was safe, tolerable and feasible for 2-5 year olds; 3. Supplementation for 9 months increased children's explicit memory performance relative to placebo; 4. Significant memory improvement was seen in 2-3 year olds but not 4-5 year olds. For 2-3 year olds, memory improvement was 21 percentage points in the choline arm compared to 2 percentage points in the placebo arm; 5. A dose ranging from 10-19 mg/kg was associated with the largest improvement in memory; 6. A very common single- nucleotide polymorphism (SNP) (rs12325817), related to endogenous choline production, appears to moderate the efficacy of choline for children with FASD. These findings directly inform the next study. Aim 1 involves evaluating a 19 mg/kg dose in 60 children with FASD, ages 2 to 5. This dosing scheme will optimize the neurocognitive benefits and further enhance tolerability of the intervention. In addition to continuing the evaluation of memory benefits from choline, Aim 2 adds measures of attention and executive function as possible additional targets. The NIH Toolbox Flanker Inhibitory Control and Attention Test and the Executive Function Scale for Early Childhood (pilot-tested during our last study) have been added. Aim 3 adds a longitudinal component - it will evaluate 40 children in the period two years after treatment to determine the permanency of choline's effects. Lastly, Aim 4 will further examine the role of known SNPs in choline synthesis as moderators to the observed treatment effects. In summary, the proposed study will continue the translation of choline's application - from experimental pre-clinical work to an evidence-based intervention for neurodevelopmental deficits in children with FASD.