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: 10471951
• 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/10471951
• 关键词: 10 year old; 5 year old; Acetylcholine; Affect; Age; Attention; Attention deficit hyperactivity disorder; Attenuated; Behavior; Brain; Brain Injuries; Brain imaging; Cells; Child; Child Behavior; Childhood; Choline; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive Therapy; 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 (Brain); Human; Impaired cognition; Individual; Intelligence; Intervention; Interview; Left; Long-Term Potentiation; Longitudinal Studies; Longterm Follow-up; Magnetic Resonance Imaging; 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; base; behavioral impairment; catalyst; choline supplementation; cholinergic; clinical decision-making; clinical implementation; cognitive benefits; cognitive function; cohort; efficacy study; executive function; first-in-human; functional improvement; improved; long term memory; memory process; morphometry; neurochemistry; neurodevelopment; neurodevelopmental effect; novel; placebo controlled trial; post intervention; pre-clinical; processing speed; programs; randomized placebo controlled trial; response; safety and feasibility; treatment duration; treatment effect; 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 尽管 FASD 具有发育迟缓和颅面异常，但对治疗方法的研究却很少。 认知缺陷是 FASD 的一个核心特征，而认知是一个巨大的公共卫生负担。 干预的自然目标是 FASD 认知的一项潜在干预措施。 营养胆碱 - 已知对海马体的大脑发育和认知有影响。 胆碱有助于增加树突分枝、增大细胞和功能变化。 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，只有少数人类。 胆碱治疗 FASD 的研究已经开展，其中大部分研究均由我们小组进行。 早期的双盲、随机、对照试验确定了我们随后的安全性和耐受性。 试验揭示了 FASD 参与者的顺序延迟记忆的有益效果（在 我们的第三项（正在进行的）研究包括一项长期研究（针对年龄较小的 [2-3 岁] 儿童，而不是年龄较大的 [3-5 岁] 儿童）。 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， 拟议的研究将包括工作记忆、长期言语记忆和多动症行为。 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两臂分组随机研究 持续时间为 3 或 6 个月，结果将直接指导未来胆碱作为药物的临床实施。 拟议的研究还将利用三个现有队列。 用于确定早期治疗效果的持久性的额外纵向研究 A 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 方法的功能性大脑影响将包括斯坦福大学- 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 安慰剂将被检查并预计反映早期的变化。 我们还将使用皮质髓磷脂图来评估胆碱的作用。 此外，我们将应用弥散加权成像来确定长期髓磷脂发育。 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。