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: 10666452
• 负责人: Michael K. Georgieff
• 金额: $ 59.63万
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666452
• 关键词: 10 year old; 5 year old; Acetylcholine; Affect; Age; Attention; Attention deficit hyperactivity disorder; Attenuated; Behavior; Behavior Therapy; Brain; Brain Injuries; Brain imaging; Cells; Child; Child Behavior; Childhood; Choline; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Craniofacial Abnormalities; Custom; Data; Delayed Memory; Development; Developmental Delay Disorders; Diagnostic; Dietary Intervention; Diffusion Magnetic Resonance Imaging; Double-Blind Method; Early treatment; Elements; Epigenetic Process; Episodic memory; Feasibility Studies; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Follow-Up Studies; Future; Gene Expression; Growth; Hippocampus; Human; Impaired cognition; Individual; Intelligence; Intervention; Interview; Left; Long-Term Potentiation; Longitudinal Studies; Longterm Follow-up; Magnetic Resonance Imaging; Maps; Measurable; Measures; Memory; Methods; Methylation; Minnesota; Myelin; Neurocognition; Neurologic; Neurons; Neurotransmitters; Nutrient; Outcome; Parents; Participant; Phase; Placebos; Prefrontal Cortex; Protocols documentation; Public Health; Randomized; Randomized, Controlled Trials; Reporting; Research; Role; Safety; Series; Short-Term Memory; Structure; Supplementation; Symptoms; System; Testing; Thinking; Time; Translating; United States National Institutes of Health; Visuospatial; Work; arm; behavioral impairment; catalyst; choline supplementation; cholinergic; clinical decision-making; clinical implementation; cognitive benefits; cognitive function; cohort; efficacy study; executive function; first-in-human; improved; long term memory; morphometry; neurochemistry; neurodevelopment; neurodevelopmental effect; neuron component; non-verbal; novel; placebo controlled trial; post intervention; postnatal; pre-clinical; processing speed; programs; randomized placebo controlled trial; response; treatment duration; treatment effect; verbal; white matter

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.

项目摘要 /摘要 胎儿酒精谱系（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 智障和颅面异常。很少有人调查目的地FASD的治疗 巨大的公共卫生伯恩。认知定义是FASD的核心特征，认知是一个 干预的自然目标。 FASD中认知的一种潜在干预是必不可少的 营养胆碱 - 已知对脑发育和认知有影响。在海马中， 胆碱有助于树突状树博，较大的细胞和功能变化。 影响胆碱能系统并改变记忆必不可少的区域的大脑结构和功能 功能，包括海马和前额叶皮层中的甲基化。只有少数人 已经进行了FASD的胆碱研究，我们的小组进行了大多数研究。我们的 早期双盲，随机，对照试验确立了安全性和耐受性。我们随后的序列 试验揭示了FASD参与者的顺序延迟记忆的有益效果（更大 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 在非语言处理中，胆碱与安慰剂的长期益处的术语随访， 工作记忆，长期言语记忆和多动症行为。拟议的研究将包括 新的临床试验与新的2-5岁儿童有FASD的新队列。而不是安慰剂 - 对照试验，它将是一项两臂块伴随研究，并累积胆碱暴露 持续时间为3或6个月。结果将直接告知将来的胆碱临床实施 神经发育干预。拟议的研究还将利用三个现有同类 有关其他纵向研究，该研究将确定早期治疗的效果持久性。一个4- 年和8年的随访研究将每个检查认知效应以及结构和结构性研究 使用高级MRI方法的功能性大脑效应。认知措施将包括斯坦福 - Binet智能量表，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 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场，以进行胆碱或 安慰剂。功能连接将进行检查，并有望反映早期的变化 补充胆碱。我们还将使用皮质髓磷脂映射来评估胆碱对 长期髓磷脂的发育。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 - 已知在FASD中被破坏。

项目成果

Neurophysiological correlates of memory change in children with fetal alcohol spectrum disorders treated with choline.

• DOI: 10.3389/fpsyg.2022.936019
• 发表时间: 2022
• 期刊: FRONTIERS IN PSYCHOLOGY
• 影响因子: 3.8
• 作者: Fuglestad, Anita J;Miller, Neely C;Fink, Birgit A;Boys, Christopher J;Eckerle, Judith K;Georgieff, Michael K;Wozniak, Jeffrey R
• 通讯作者: Wozniak, Jeffrey R