Postnatal Choline Supplementation in Children with Prenatal Alcohol Exposure

描述（由申请人提供）：目前，关于胎儿酒精谱系障碍（FASD）个体干预的文献非常有限，只有两项已发表的随机对照试验，但有一些有希望的新治疗方案尚未应用于人类。最近的临床前研究已经戏剧性地证明，在啮齿类动物中，出生前甚至出生后，迟至第21-30天（相当于人类童年）的饮食胆碱补充，减弱了与出生前酒精暴露相关的记忆和行为缺陷（托马斯等人，2007;托马斯等人，2000年）。我们提出了一个为期两年的项目，以评估的可行性和耐受性，出生前酒精暴露的幼儿出生后胆碱补充剂，随后进行了为期三年的双盲，安慰剂对照的试点研究，检查胆碱补充剂在改善这些儿童的认知和行为功能的疗效。在R21可行性阶段，20名年龄在12个月至54个月之间的儿童将被随机分配到9个月的胆碱补充剂或安慰剂组。6个月和9个月的随访访视将包括父母的行为评级、认知测量（包括早期学习的马伦量表和诱发模仿（EI）海马范例）和电生理测量（包括髓鞘形成相关处理速度的VEP测量）。根据R21阶段收集的数据，将修改研究设计，并在R33阶段以更大规模实施。在R33阶段，40名儿童将随机接受胆碱补充剂或安慰剂。随访措施将与R21研究相同或略有修改。研究结果将用于设计一个更大的，全面的临床试验，以测试出生后胆碱补充剂在出生前酒精暴露的幼儿中的疗效。考虑到对海马发育、髓鞘形成和大脑发育的其他基本方面的潜在影响，这种治疗可能对许多其他神经发育障碍具有显著的适用性。 公共卫生相关性：众所周知，怀孕期间饮酒会导致儿童永久性脑损伤，但目前还没有确定的治疗方法。最近，动物研究表明，出生后补充胆碱（一种在许多食物中发现的必需营养素）可以减轻暴露于酒精的动物中常见的认知和行为缺陷。尚未进行儿童胆碱补充剂的人体研究。这项拟议的研究将评估在特定的发育窗口期间，当儿童的大脑保持一定的可塑性时，胆碱补充剂是否能够减轻患有胎儿酒精谱系障碍（FASD）的儿童常见的思维，记忆，处理速度和行为方面的缺陷。我们希望这项研究将提供有关胆碱补充剂在1-5岁儿童中的实用性的重要信息，并将提供其有效性的初步估计。

DESCRIPTION (provided by applicant): At present, the literature on interventions for individuals with Fetal Alcohol Spectrum Disorders (FASD) is very limited, with only two published randomized controlled trials, yet there are promising new treatment options that have not been applied in humans. Recent pre-clinical studies have dramatically demonstrated that dietary choline supplementation pre-natally and even post-natally, as late as days 21-30 in the rodent (equivalent to human childhood), attenuates the memory and behavioral deficits associated with prenatal alcohol exposure (Thomas et al., 2007; Thomas et al., 2000). We propose a two-year project to evaluate the feasibility and tolerability of post-natal choline supplementation in young children with pre-natal alcohol exposure followed by a three-year double-blind, placebo-controlled pilot study examining the efficacy of choline supplementation in improving the cognitive and behavioral functioning of these children. In the R21 feasibility phase, 20 children between the ages of 12 months and 54 months will be randomized to nine months of choline supplementation or placebo. Follow-up visits at 6 months and 9 months will include parent ratings of behavior, cognitive measures including the Mullen Scales of Early Learning and an elicited imitation (EI) hippocampal paradigm, and electrophysiological measures including a VEP measure of myelination-associated processing speed. Based on data collected in the R21 phase, the study design will be modified and implemented on a larger scale in the R33 phase. During the R33 phase, 40 children will be randomized to choline supplementation or placebo. Follow-up measures will be the same or slightly modified based on the R21 study. Results of the studies will be used to design a larger, full-scale clinical trial to test the efficacy of post-natal choline supplementation in young children with pre-natal alcohol exposure. Given the potential effects on hippocampal development, myelination, and other basic aspects of brain development, this treatment may have significant applicability to a host of other neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Alcohol consumption during pregnancy is known to contribute to permanent brain damage in the child, yet there are no established treatments. Recently, animal studies have demonstrated that postnatal supplementation with choline, an essential nutrient found in many foods, can attenuate the cognitive and behavioral deficits typically seen in alcohol-exposed animals. A human study of choline supplementation in children has not yet been done. The proposed study will evaluate if choline supplementation during a specific developmental window when the child's brain remains somewhat plastic is able to attenuate the deficits in thinking, memory, processing speed, and behavior that are common in children with Fetal Alcohol Spectrum Disorders (FASD). We expect that this study will provide important information about the practicality of choline supplementation in children 1-5 years of age and will provide initial estimates of its effectiveness.