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）个体干预措施的文献非常有限，只有两项已发表的随机对照试验，但有前景的新治疗方案尚未应用于人类。最近的临床前研究已经显著地证明，在啮齿动物的产前甚至产后，直到21-30天（相当于人类的童年），饮食中补充胆碱可以减轻与产前酒精暴露相关的记忆和行为缺陷（Thomas et al., 2007; Thomas et al., 2000）。我们提出了一个为期两年的项目，以评估产后补充胆碱对产前酒精暴露的幼儿的可行性和耐受性，随后进行了一项为期三年的双盲、安慰剂对照的试点研究，以检验补充胆碱对改善这些儿童认知和行为功能的功效。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为9个月的胆碱补充组或安慰剂组。6个月和9个月的随访将包括父母行为评分、认知测量（包括马伦早期学习量表和诱导模仿（EI）海马范式）和电生理测量（包括VEP测量髓鞘相关处理速度）。基于R21阶段收集的数据，研究设计将在R33阶段进行修改和更大规模的实施。在R33阶段，40名儿童将被随机分配到胆碱补充组或安慰剂组。随访措施与R21研究相同或略有修改。这些研究的结果将用于设计一个更大的、全面的临床试验，以测试产后补充胆碱对产前酒精暴露的幼儿的疗效。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重要的适用性。

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.