Choline Supplementation as a Neurodevelopmental Intervention in Fetal Alcohol Spectrum Disorders

项目概要/摘要 胎儿酒精谱系障碍 (FASD) 包括产前酒精造成的一系列影响 暴露（PAE），包括神经系统异常、认知和行为障碍、生长 发育迟缓和颅面异常。尽管 FASD 的治疗方法很少被研究 巨大的公共卫生负担。认知缺陷是 FASD 的核心特征，而认知是 干预的自然目标。对 FASD 认知的一种潜在干预措施是 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分枝、增大细胞和功能变化。胆碱 影响胆碱能系统并改变记忆必需区域的大脑结构和功能 功能，包括海马体和前额皮质的甲基化。只有极少数人类 已经开展了针对 FASD 的胆碱研究，其中大部分研究均由我们小组进行。我们的 早期的双盲、随机、对照试验确立了安全性和耐受性。我们后续的 试验揭示了 FASD 参与者的顺序延迟记忆的有益效果（在 年龄较小的 [2-3 岁] 儿童，而不是年龄较大的 [3-5 岁] 儿童）。我们的第三项（正在进行的）研究包括一项长期研究 长期随访证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、长期言语记忆和多动症行为。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。而不是安慰剂—— 对照试验，这将是一项累积胆碱暴露的双臂分组随机研究 持续时间为3或6个月。结果将直接为胆碱作为药物的未来临床应用提供信息 神经发育干预。拟议的研究还将利用三个现有队列 进行额外的纵向研究，以确定早期治疗效果的持久性。一个 4- 年和 8 年的后续研究将分别检查认知效果以及结构和 使用先进的 MRI 方法对大脑功能产生影响。认知测量将包括斯坦福大学 比奈智力量表、引出模仿记忆测试、NIH Toolbox Flanker 测试和图片 序列记忆测试和明尼苏达执行功能量表。我们将检查胆碱 使用家长报告（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域在胆碱或 安慰剂。将检查功能连接性，并预计反映早期的变化 补充胆碱。我们还将使用皮质髓磷脂图来评估胆碱对 长期髓磷脂发育。此外，我们将应用扩散加权成像来确定 胆碱对白质微观结构的影响——众所周知，胎儿酒精谱系障碍 (FASD) 中白质微观结构会受到破坏。

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.