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)包括由产前酒精引起的一系列影响 暴露(PAE)，包括神经异常、认知和行为障碍、生长 发育迟缓和头面部畸形。尽管FASD的治疗方法很少，但很少有人研究 巨大的公共卫生负担。认知缺陷是FASD的核心特征，而认知是 自然成为干预的目标。对FASD认知的一种潜在干预是必要的 营养胆碱-已知对大脑发育和认知有影响。在海马体中， 胆碱可导致树突状分支增多、细胞变大和功能改变。胆碱 影响胆碱能系统，改变大脑记忆必需区域的结构和功能 功能，包括海马体和前额叶皮质中的甲基化。只有少数几个人类 针对FASD的胆碱研究已经开展，我们小组已经进行了大部分研究。我们的 早期的双盲、随机、对照试验确定了安全性和耐受性。我们的后续行动 试验显示，FASD参与者对顺序延迟记忆的有益影响(在 年龄较小的[2-3岁]，而不是较大的[3-5岁]儿童)。我们的第三项(正在进行的)研究包括一个长期的- 长期随访显示在非语言处理中胆碱与安慰剂相比有长期益处， 工作记忆、长期言语记忆和多动症行为。拟议的研究将包括 对患有FASD的2-5岁儿童进行新的临床试验。而不是安慰剂- 对照试验，这将是一项累积胆碱暴露的双臂区组随机研究 持续时间为3或6个月。结果将直接指导胆碱作为一种药物在未来的临床应用 神经发育干预。拟议的研究还将利用现有的三个队列 用于其他纵向研究，以确定早期治疗效果的持久性。A 4- 为期一年和八年的跟踪研究将分别检查认知影响以及结构和 使用先进的核磁共振方法实现脑功能效应。认知测量将包括斯坦福大学- 比奈智力量表、引出模仿记忆测验、NIH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。我们会检查胆碱 使用父母报告(CBCL)和结构化诊断访谈(KSADS)对行为的影响。 将检查选定的海马子区在胆碱或 安慰剂。将检查功能连通性，并预计会反映早期的变化 补充胆碱。我们还将使用皮质髓鞘成像来评估胆碱对 长期的髓鞘发育。此外，我们将应用扩散加权成像来确定 胆碱对脑白质微结构的影响--这是已知在FASD中被破坏的。

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. Few treatments have been investigated despite FASD’s tremendous public health burden. Cognitive deficits are a core feature of FASD, and cognition is a natural target for intervention. One potential intervention for cognition in FASD is the essential nutrient choline - known to have effects on brain development and cognition. 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 long-term benefits for choline vs. placebo in non-verbal processing, working memory, long-term verbal memory, and ADHD behavior. 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, it will be a two-arm block-randomized study with cumulative choline exposure durations of 3 or 6 months. Results will directly inform future clinical implementation of choline as a neurodevelopmental intervention. The proposed studies will also capitalize on three existing cohorts for additional longitudinal studies that will determine durability of effects from 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 advanced 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 (CBCL) and a structured diagnostic interview (KSADS). Select hippocampal sub-fields will be examined for volumetric improvements following choline or placebo. Functional connectivity will be examined and is expected to reflect changes from early choline supplementation. We will also use cortical myelin mapping to evaluate choline’s effect on long-term myelin development. In addition, we will apply diffusion-weighted imaging to determine choline’s effect on white matter microstructure – which is known to be disrupted in FASD.