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.

项目概要/摘要 胎儿酒精谱系障碍 (FASD) 包括产前酒精暴露造成的一系列影响 (PAE) 包括神经系统异常、认知和行为障碍、生长迟缓和 颅面异常。尽管 FASD 的公共卫生影响巨大，但对治疗方法的研究却很少 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性功能、社交技能和独立生活方面的问题。一 对 FASD 认知障碍的潜在干预措施是必需营养素胆碱 - 众所周知，胆碱可以 对大脑发育和新兴认知有许多直接影响。胆碱的影响 广泛的神经发育，尤其是海马体；胆碱有助于增加树突 树枝化、细胞变大和功能变化。胆碱影响胆碱能系统并改变大脑 记忆功能必需区域的结构和功能，包括海马体的甲基化 和前额皮质。仅进行了少数针对胎儿酒精谱系障碍 (FASD) 的人类胆碱研究，我们的团队 已经进行了其中的大部分。我们早期的双盲、随机、对照试验确立了安全性和 耐受性。我们随后的试验揭示了对连续记忆延迟的参与者的有益影响 FASD（年龄较小的 [2-3 岁] 儿童比年龄较大的 [3-5 岁] 儿童更严重）。我们的第三项（正在进行的）研究包括 一项长期随访表明，与安慰剂相比，胆碱在非语言处理方面具有永久的益处， 工作记忆、长期言语记忆和多动症行为。拟议的研究将利用 三个现有队列进行额外的纵向研究，有可能显示持久性 早期治疗的效果。为期 4 年和 8 年的随访研究将分别检查认知影响以及 使用先进的 MRI 方法对大脑结构和功能产生影响。认知测量将包括 斯坦福-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。我们将检查胆碱对 使用家长报告（儿童行为检查表）的行为。海马体将被特别检查 胆碱后体积的变化，包括亚结构水平的变化。海马 连接性将受到检查，预计将反映早期胆碱补充带来的变化。最后， 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。 这将是一项三臂剂量探索研究，而不是安慰剂对照试验，参与者将接受 胆碱三个持续时间之一（3、6 或 9 个月）。试验结果将直接告知未来的临床 实施胆碱作为神经发育干预措施。

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