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: 9274124
• 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/9274124
• 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; Participant; Performance; Phosphatidylethanolamine N-Methyltransferase; Pilot Projects; Placebo Control; Placebos; Plasticizers; Population; Pregnancy; Production; Public Health; Publishing; Randomized; Reporting; Role; Safety; Scheme; Single Nucleotide Polymorphism; 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 study; efficacy testing; executive function; flexibility; improved; memory process; pre-clinical; processing speed; public health relevance; response; sustained attention; treatment effect; trimethyloxamine

 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(由申请人提供)：公布的数据表明，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)。尽管公共卫生负担沉重，但还没有临床试验试图直接解决FASD中使人虚弱的神经发育缺陷。广泛的临床前工作(Thomas等人等)提供了证据，表明补充胆碱在减轻动物模型中由产前酒精暴露引起的神经发育缺陷方面是有效的。我们团队已经采取了初步步骤，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验性研究，以确保20名FASD儿童服用胆碱补充的可行性、耐受性和安全性(Fuglestad等人，2013年)。接下来，我们完成了一项另外40名参与者的研究，目标是为幼儿建立目标剂量，测试记忆领域的有效性，并确定胆碱影响的发育窗口(详细信息见《初步研究》)。简而言之，我们的初步数据显示：1.患有FASD的儿童平均摄入不足的胆碱；2.对于2-5岁的儿童来说，补充胆碱是安全、可耐受和可行的；3.与安慰剂相比，补充9个月可以提高儿童的外显记忆表现；4.在2-3岁的儿童中，记忆力得到了显著的改善，但4-5岁的儿童没有。对于2-3岁的儿童，胆碱组的记忆力改善为21个百分点，而安慰剂组为2个百分点；5.10-19毫克/公斤的剂量与记忆力的改善最大相关；6.一个非常常见的单核苷酸多态(SNP)(Rs12325817)，与内源性胆碱的产生有关，似乎缓和了胆碱对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评估60名2-5岁FASD儿童的19 mg/kg剂量。该剂量方案将优化神经认知益处，并进一步提高干预的耐受性。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。NIH工具箱的侧翼抑制控制和注意测试和早期儿童执行功能量表(在我们上一次研究期间进行了试点测试)已经增加。目标3增加了一个纵向部分--它将在治疗后两年内评估40名儿童，以确定胆碱作用的永久性。最后，目标4将进一步研究已知的SNPs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，这项拟议的研究将继续将胆碱的应用从实验性的临床前工作转变为对FASD儿童神经发育缺陷的循证干预。