Choline Supplementation as a Neurodevelopmental Intervention in Fetal Alcohol Spectrum Disorders

补充胆碱作为胎儿酒精谱系障碍的神经发育干预措施

• 批准号: 9126393
• 负责人: Michael K. Georgieff
• 金额: $ 30.78万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126393
• 关键词: 3 year old; 5 year old; Address; Aftercare; Age; Alleles; Animal Model; Attention; Attenuated; Behavior; Brain; Brain Injuries; Child; Choline; Clinical Trials; Cognitive; Data; Development; Diet; Dose; Double-Blind Method; Ensure; Equilibrium; Evaluation; Evidence based intervention; Feasibility Studies; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Genotype; Goals; Human; Individual; Intervention; Longevity; Measures; Memory; Micronutrients; Neurocognitive; Neurodevelopmental Deficit; Neurodevelopmental Disorder; Nutrient; Odors; Oxides; Participant; Performance; Phosphatidylethanolamine N-Methyltransferase; Pilot Projects; Placebo Control; Placebos; Population; Pregnancy; Production; Public Health; Publishing; Randomized; Reporting; Role; Safety; Scheme; Single Nucleotide Polymorphism; Sorting - Cell Movement; Supplementation; Testing; Thinking; Time; Translating; Translational Research; Translations; United States National Institutes of Health; Work; alcohol consumption during pregnancy; arm; choline supplementation; cognitive development; cognitive function; design; dosage; double-blind placebo controlled trial; early childhood; efficacy testing; executive function; flexibility; improved; memory process; pre-clinical; processing speed; public health relevance; response; sustained attention; treatment effect; trimethylamine

 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.

 描述（由适用提供）：已发布的数据表明，美国2-5％的人群患有胎儿酒精谱系障碍（FASD） - 一组由产前酒精暴露引起的物理异常和神经发育定义（May＆Gossage，2001年）。尽管Burnen拥有深远的公共卫生，但尚无临床试验试图直接解决FASD如此令人衰弱的神经发育定义。广泛的临床工作（Thomas等人等）提供了证据，表明补充胆碱可有效地减弱动物模型中由产前酒精暴露引起的神经发育定义。我们的小组采取了最初的步骤，将这项工作通过两个随机，双盲，安慰剂对照试验转化为人类。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等，2013）。接下来，我们完成了一项针对40名参与者的研究，其目标是为幼儿建立目标剂量，测试记忆领域的有效性，并确定胆碱作用的发展窗口（在“初步研究”中详细介绍）。简而言之，我们的试点数据显示：1。儿童平均食用饮食胆碱不足； 2。补充胆碱是安全的，可容忍的，可容忍和可行。 3。补充9个月，相对于安慰剂，增加了儿童的明确记忆表现； 4。在2-3岁的孩子中看到了显着的记忆力，但没有4-5岁的孩子。对于2-3岁的年轻人，胆碱臂的记忆力提高为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，与记忆的最大改善有关； 6。一种非常常见的单核苷酸多态性（SNP）（rs12325817），与内源性胆碱产生有关，似乎适应FASD儿童的胆碱效率。这些发现直接告知下一项研究。 AIM 1涉及评估60名FASD儿童（2至5岁）的19 mg/kg剂量。这种给药方案将优化神经认知益处，并进一步提高干预措施的耐受性。 AIM 2除了继续评估胆碱的记忆益处，还增加了注意力和执行功能的测量，作为可能的其他目标。 NIH工具箱侧翼抑制性控制和注意力测试以及幼儿期的执行功能量表（在我们上次研究中进行了试验测试）。 AIM 3添加了纵向成分 - 在治疗后的两年中，它将评估40名儿童，以确定胆碱作用的永久性。最后，AIM 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。总而言之，拟议的研究将继续对胆碱的应用转换 - 从实验性临床前工作到基于证据的FASD儿童神经发育缺陷的干预措施。