Choline Supplementation as a Neurodevelopmental Intervention in Fetal Alcohol Spectrum Disorders

补充胆碱作为胎儿酒精谱系障碍的神经发育干预措施

• 批准号: 10250653
• 负责人: Michael K. Georgieff
• 金额: $ 15.42万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250653
• 关键词: 5 year old; Acetylcholine; Adolescence; Affect; Age; Attention; Attention deficit hyperactivity disorder; Attenuated; Behavior; Brain; Brain Injuries; Brain imaging; Cells; Child; Child Behavior Checklist; Childhood; Choline; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive Therapy; Craniofacial Abnormalities; Custom; Data; Delayed Memory; Development; Developmental Delay Disorders; Dietary Intervention; Dose; Double-Blind Method; Early treatment; Epigenetic Process; Feasibility Studies; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Follow-Up Studies; Future; Gene Expression; Goals; Growth; Growth and Development function; Hippocampus (Brain); Homing; Human; Impaired cognition; Independent Living; Individual; Intelligence; Intervention; Left; Life; Long-Term Potentiation; Longitudinal Studies; Longterm Follow-up; Magnetic Resonance Imaging; Measurable; Measures; Memory; Methods; Methylation; Minnesota; Myelin; Neurocognitive; Neurocognitive Deficit; Neurologic; Neurons; Neuropsychology; Neurotransmitters; Nutrient; Outcome; Parents; Participant; Phase; Placebos; Prefrontal Cortex; Public Health; Publishing; Randomized Controlled Trials; Reporting; Research; Research Project Grants; Role; Safety; Short-Term Memory; Structure; Supplementation; Symptoms; System; Testing; Thinking; Time; Translating; United States National Institutes of Health; Visuospatial; Work; arm; base; behavioral impairment; brain morphology; catalyst; choline supplementation; cholinergic; clinical implementation; cognitive benefits; cognitive function; cohort; design; early adolescence; efficacy study; executive function; first-in-human; follow-up; functional improvement; improved; long term memory; memory process; neurochemistry; neurodevelopment; neurodevelopmental effect; novel; placebo controlled trial; post intervention; postnatal; pre-clinical; processing speed; programs; randomized placebo controlled trial; response; safety and feasibility; skills; social skills; treatment effect

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.

项目总结/摘要 胎儿酒精谱系障碍（FASD）包括产前酒精暴露引起的一系列影响 (PAE)包括神经异常、认知和行为障碍、生长迟缓，以及 颅面畸形尽管FASD的巨大的公共健康， 负担神经认知缺陷是FASD的核心特征，认知是干预的天然目标 因为缺陷会导致适应功能、社交技能和独立生活的问题。一 对FASD认知障碍的潜在干预是必需的营养素胆碱-已知胆碱 对大脑发育和认知能力的形成有许多直接的影响。胆碱影响 神经发育广泛，但特别是在海马;胆碱有助于增加树突状细胞 树枝化、细胞变大和功能改变。胆碱影响胆碱能系统并改变大脑 记忆功能所必需区域的结构和功能，包括海马体中的甲基化 和前额叶皮层只有少数人类胆碱研究FASD已经进行，我们的小组 已经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， 耐受性我们随后的试验显示， FASD（年龄较小[2-3岁]的儿童比年龄较大[3-5岁]的儿童更严重）。我们的第三项（正在进行的）研究包括 一项长期随访显示，胆碱与安慰剂相比，在非语言处理方面具有永久性益处， 工作记忆、长期非文字记忆和ADHD行为。拟议的研究将利用 三个现有队列进行额外的纵向研究，这些研究有可能显示 早期治疗的效果。一项为期4年和8年的随访研究将分别检查认知效果以及 结构和功能的大脑影响使用先进的MRI方法。认知测量将包括 斯坦福-比奈智力量表、诱发性模仿记忆测验、美国国立卫生研究院的Flanker测验和图片 序列记忆测试和明尼苏达执行功能量表。我们将研究胆碱对 使用家长报告（儿童行为检查表）。特别是海马， 胆碱后的体积变化，包括亚结构水平的变化。海马 将检查连接性，并预计反映早期胆碱补充的变化。最后， 拟议的研究将包括一项新的临床试验，对2-5岁的FASD儿童进行新的队列研究。 这不是一项安慰剂对照试验，而是一项3组剂量探索研究，受试者将接受 胆碱三个持续时间之一（3，6，或9个月）。试验结果将直接为未来的临床研究提供信息。 胆碱作为神经发育干预的实施。

项目成果

Early delay of gratification predicts later inhibitory control and academic performance in children with prenatal alcohol exposure.

• DOI: 10.1080/09297049.2020.1798372
• 发表时间: 2021-01
• 期刊: Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence
• 作者: de Water E;Krueger AM;Lindgren CW;Fuglestad AJ;Rockhold MN;Sandness KE;Eckerle JK;Fink BA;Boys CJ;Wozniak JR
• 通讯作者: Wozniak JR

Prenatal and Postnatal Choline Supplementation in Fetal Alcohol Spectrum Disorder.

• DOI: 10.3390/nu14030688
• 发表时间: 2022-02-06
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Ernst AM;Gimbel BA;de Water E;Eckerle JK;Radke JP;Georgieff MK;Wozniak JR
• 通讯作者: Wozniak JR