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.

项目摘要 /摘要 胎儿酒精谱障碍（FASD）包括产前酒精暴露引起的一系列影响 （PAE），包括神经系统异常，认知和行为障碍，增长障碍以及 颅面异常。尽管FASD巨大的公共卫生，但很少有人调查治疗 负担。神经认知定义是FASD的核心特征，认知是干预的自然目标 因为定义有助于自适应功能，社交技能和独立生活的问题。一 FASD认知障碍的潜在干预是必需的营养胆碱 - 已知这是已知的 对大脑发育和新兴认知有许多直接影响。胆碱的影响 神经发育广泛，尤其是在海马中；胆碱有助于树突状增加 树木化，较大的细胞和功能变化。胆碱会影响胆碱能系统并改变大脑 记忆功能所必需的区域的结构和功能，包括海马中的甲基化 和前额叶皮层。仅进行了少数人类的FASD研究，我们的小组 已经进行了大多数。我们早期的双盲，随机，对照试验确定了安全性和 耐受性。我们随后的试验揭示了参与者的顺序延迟记忆的有益效果 FASD（年轻[2-3岁]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 长期随访，证明了胆碱与安慰剂在非语言加工中的永久益处， 工作记忆，长期言语记忆和多动症行为。拟议的研究将大写 三个现有的队列进行其他纵向研究，有可能显示 早期治疗的影响。一项为期4年和8年的随访研究将每个检查认知效应以及 使用先进的MRI方法的结构和功能性脑作用。认知措施将包括 Stanford-Binet智力量表，引起的模仿记忆测试，NIH工具箱侧翼测试和图片 序列记忆测试和明尼苏达州执行功能量表。我们将检查胆碱对 使用家长报告（儿童行为清单）的行为。特别是检查海马 胆碱后的体积变化，包括在子结构水平上的变化。海马 连通性将进行检查，并有望反映早期补充胆碱的变化。最后， 拟议的研究将包括一项新的临床试验，其中包括2-5岁的FASD儿童的新队列。 这将是一项3臂剂量查找研究，而不是安慰剂对照试验 胆碱为三个持续时间之一（3、6或9个月）。试验的结果将直接告知未来的临床 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