Choline Supplementation as a Neurodevelopmental Intervention in Fetal Alcohol Spectrum Disorders

项目摘要/摘要 胎儿酒精谱系障碍(FASD)包括一系列由产前酒精暴露引起的影响 (PAE)包括神经异常、认知和行为障碍、生长迟缓和 头面部畸形。尽管FASD有巨大的公共健康，但很少有人研究过治疗方法 负担。神经认知缺陷是FASD的核心特征，认知是干预的自然目标 因为缺陷会导致适应能力、社交技能和独立生活方面的问题。一 对FASD认知障碍的潜在干预是必要的营养胆碱--众所周知 对大脑发育和新出现的认知有许多直接影响。胆碱影响 神经发育广泛，但特别是在海马区；胆碱有助于增加树突状细胞 树枝状，较大的细胞和功能改变。胆碱影响胆碱能系统并改变大脑 记忆功能的关键区域的结构和功能，包括海马区的甲基化 和前额叶皮质。只有为数不多的人类胆碱对FASD进行了研究，我们小组 已经进行了大部分的测试。我们早期的双盲、随机、对照试验确定了安全性和 耐受性。我们随后的试验显示了对顺序延迟记忆的有益影响 FASD(在更小的[2-3岁]儿童中更严重，而不是在较大的[3-5岁]儿童中)。我们的第三项(正在进行的)研究包括 一项长期随访显示，在非语言处理方面，胆碱与安慰剂相比具有永久性的好处， 工作记忆、长期言语记忆和多动症行为。拟议的研究将利用 其他纵向研究的三个现有队列，有可能表明 早期治疗的效果。一项为期4年和8年的跟踪研究将分别检查认知影响以及 使用先进的核磁共振方法研究大脑的结构和功能效应。认知测量将包括 斯坦福-比奈智力量表、诱发模仿记忆测验、美国国立卫生研究院工具箱侧翼测验和图画测验 序列记忆测验和明尼苏达执行功能量表。我们将研究胆碱对人体的影响 使用父母的行为报告(儿童行为核对表)。特别是海马体将被检查 胆碱后的体积改变，包括亚结构水平的改变。海马区 将检查连接性，预计将反映早期补充胆碱后的变化。最后， 拟议的研究将包括一项新的临床试验，对象是患有FASD的2-5岁儿童的新队列。 这将不是一项安慰剂对照试验，而是一项三臂剂量发现研究，参与者将接受 胆碱，持续3个月、6个月或9个月。试验结果将直接通知未来的临床 胆碱作为神经发育干预的实施。

PROJECT SUMMARY / ABSTRACT Fetal alcohol spectrum disorders (FASDs) comprise a range of effects resulting from prenatal alcohol exposure (PAE) including neurological abnormalities, cognitive and behavioral impairments, growth retardation, and craniofacial anomalies. Very few treatments have been investigated despite FASD’s tremendous public health burden. Neurocognitive deficits are a core feature of FASD, and cognition is a natural target for intervention because deficits contribute to problems with adaptive functioning, social skills, and independent living. One potential intervention for the cognitive impairments in FASD is the essential nutrient choline - which is known to have numerous direct effects on brain development and emerging cognition. Choline impacts neurodevelopment broadly, but especially in the hippocampus; choline contributes to increased dendritic arborization, larger cells, and functional changes. Choline affects the cholinergic system and alters brain structure and function in regions essential for memory functioning, including methylation in the hippocampus and prefrontal cortex. Only a handful of human choline studies for FASD have been undertaken and our group has conducted most of them. Our early double-blind, randomized, controlled trial established safety and tolerability. Our subsequent trial revealed beneficial effects for sequential delayed memory in participants with FASD (greater in younger [ages 2-3] rather than older [ages 3-5] children). Our third (ongoing) study included a long-term follow-up that demonstrated permanent benefits for choline vs. placebo in non-verbal processing, working memory, long-term verbal memory, and ADHD behavior. The proposed studies will capitalize on three existing cohorts for additional longitudinal studies that have the potential to show permanency of the effects of early treatment. A 4-year and 8-year follow-up study will each examine cognitive effects as well as structural and functional brain effects using advance MRI methods. Cognitive measures will include the Stanford-Binet Intelligence Scale, the Elicited Imitation memory test, the NIH Toolbox Flanker test and Picture Sequence Memory Test, and the Minnesota Executive Function Scale. We will examine choline effects on behavior using parent-report (Child Behavior Checklist). Hippocampus in particular will be examined for volumetric alterations following choline, including alterations at the level of sub-structures. Hippocampal connectivity will be examined and is expected to reflect changes from early choline supplementation. Lastly, the proposed studies will include a new clinical trial with a new cohort of 2-5 year old children with FASD. Rather than a placebo-controlled trial, this will be a 3-arm dose finding study in which participants will receive choline for one of three durations (3, 6, or 9 months). Results of the trial will directly inform future clinical implementation of choline as a neurodevelopmental intervention.