Choline Supplementation as a Neurodevelopmental Intervention in Fetal Alcohol Spectrum Disorders

项目总结/摘要 胎儿酒精谱系障碍（FASD）包括产前酒精引起的一系列影响 暴露（PAE），包括神经系统异常、认知和行为障碍、生长 发育迟缓和颅面畸形尽管FASD的治疗方法很少， 巨大的公共卫生负担。认知缺陷是FASD的核心特征，而认知是FASD的一个重要特征。 自然是干预的对象。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， 胆碱有助于增加树突状分支、更大的细胞和功能变化。胆碱 影响胆碱能系统，改变大脑结构和记忆关键区域的功能 功能，包括海马体和前额皮质的甲基化。只有少数人类 胆碱对FASD的研究已经进行，我们的小组进行了其中的大部分。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 一项试验显示，FASD参与者的顺序延迟记忆（ 年龄较小[2-3岁]而不是年龄较大[3-5岁]的儿童）。我们的第三项（正在进行的）研究包括一项长期的- 长期随访表明胆碱与安慰剂相比在非语言处理方面具有长期益处， 工作记忆、长期非文字记忆和ADHD行为。拟议的研究将包括 一项针对2-5岁FASD儿童新队列的新临床试验。不是安慰剂- 对照试验，这将是一项具有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。结果将直接告知未来胆碱作为一种 神经发育干预拟议的研究还将利用现有的三个队列 进行额外的纵向研究，以确定早期治疗效果的持久性。A 4- 一年和8年的随访研究将分别检查认知效果以及结构和 大脑功能的影响。认知测量将包括斯坦福大学- Binet智力量表、诱发模仿记忆测验、NIH Flanker测验和图片测验 序列记忆测试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。 将检查选择的海马子野，以确定胆碱或 安慰剂将检查功能连接，并预计将反映早期的变化 胆碱补充剂我们还将使用皮层髓鞘映射来评估胆碱对神经元的影响。 长期髓鞘发育。此外，我们将应用弥散加权成像来确定 胆碱对白色物质微观结构的影响-已知在FASD中被破坏。

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.