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Fetal Neuroprotection by choline supplementation in heavy drinking pregnant women

大量饮酒孕妇补充胆碱对胎儿神经的保护

基本信息

批准号：
10583742
负责人：
ROBERT COLIN CARTER
金额：
$ 48.9万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583742
关键词：
Acetylcholine Adverse effects Affect Age Months Alcohols Anatomy Animals Anisotropy Area Award Birth Brain Brain region Cell membrane Cells Cellular Structures Choline Clinical Clinical Trials Cognitive Cognitive deficits Collaborations Communities Community Practice Counseling Coupled DNA Methylation Data Development Dietary Supplementation Diffusion Diffusion Magnetic Resonance Imaging Disadvantaged Dose Double-Blind Method Down Syndrome Energy Metabolism Enrollment Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal Development Fetal alcohol effects Fetus Funding General Hospitals Gestational Age Grant Growth Growth and Development function HIV Head circumference Heavy Drinking Hippocampus Infant Intake Intellectual functioning disability Intervention Investments Knowledge Learning Length Magnetic Resonance Imaging Massachusetts Measurable Measurement Measures Mediating Metabolic Metabolism Modeling N-acetylaspartate National Institute on Alcohol Abuse and Alcoholism Neonatal Nervous System Trauma Neural Tube Closure Neurocognitive Neurotransmitters Newborn Infant Nutrient Nutritional Nutritional status Outcome Perinatal Placebo Control Placebos Pregnancy Pregnant Women Prevalence Province Public Health Randomized Research Personnel Research Priority Rett Syndrome Role Short-Term Memory South Africa Structure Supplementation Test Result Treatment Efficacy United States National Institutes of Health Universities Weight Woman arm autism spectrum disorder brain volume choline supplementation cognitive development cognitive testing conditioned fear deep learning dietary drinking eyeblink conditioning fetal high risk human study improved infant outcome information processing magnetic resonance spectroscopic imaging medical schools memory recognition metabolic imaging methyl group multimodality neonatal brain neonatal magnetic resonance imaging neonate neurodevelopment neuroimaging neuromechanism neuroprotection postnatal prenatal prenatal intervention primary outcome processing speed psychosocial randomized placebo controlled trial randomized placebo-controlled clinical trial randomized, clinical trials recruit remediation rural area secondary outcome spectrograph standard of care white matter

项目摘要

PROJECT SUMMARY Fetal alcohol spectrum disorders represent the most prevalent cause of preventable intellectual disability. Prevalence in high-risk communities in the Western Cape region of South Africa may be as high as 20.9%. Prenatal alcohol exposure (PAE) impacts the developing brain, resulting in cognitive deficits, growth restriction and structural brain changes. Despite psychosocial interventions, heavy drinking during pregnancy continues to be a major public health challenge in the Western Cape, U.S. and worldwide. In a recent preliminary study, we showed that high dose maternal choline supplementation during pregnancy mitigates adverse effects of PAE on infant growth and cognitive development, as well as neonatal brain structure. This proposal will add on to a recently NIH-funded fully-powered, double-blind, randomized placebo-controlled trial in which 288 heavy drinking Western Cape women will be given choline or placebo during pregnancy and infants will be assessed through 12 months of age. We propose the addition of neonatal neuroimaging, including brain anatomical, diffusion and metabolic spectral imaging, to examine neural mechanisms mediating the beneficial effects of maternal choline supplementation on infant developmental outcomes. We hypothesize that choline supplementation in heavy drinking pregnant women will reduce the adverse impact of PAE on the developing fetal brain by normalizing anatomical development, connectivity, and brain energy metabolism. Brain development is energy demanding and highly sensitive to nutritional reserves. Alcohol measurably disrupts brain metabolites. Choline is a precursor to acetylcholine, a metabolite critical in healthy cell development. Depletion of choline reserves coupled with alcohol-induced disruption adversely affects fetal brain development. Our preliminary infant brain anatomical data show clear developmental effects of PAE and the mitigating effects of maternal choline supplementation. We will combine the clinical and nutritional information and infant cognitive test results from the clinical trial with the brain anatomical, connectivity and metabolic measurements from the current study to augment our understanding of the mechanistic underpinnings of the neuroprotective benefits of prenatal maternal choline supplementation on the developing fetus in the setting of PAE. We will develop capacity for acquiring region-specific neurometabolic information using magnetic resonance spectroscopic imaging (MRSI) and deep learning to identify neonatal brain regions. This project builds on the decades-long collaborations between Drs. Meintjes (University of Cape Town), S. and J. Jacobson (Wayne State University School of Medicine), van der Kouwe (Massachusetts General Hospital) and Carter (Columbia University). Drs. Choi and Lee, experts on measuring energy metabolism in prescribed brain regions using MRSI, will serve as consultants on this study.

项目摘要胎儿酒精谱系障碍是可预防的智力残疾的最常见原因。在南非西开普省地区的高风险社区，患病率可能高达20.9%。产前酒精暴露（PAE）影响发育中的大脑，导致认知缺陷，生长受限和大脑结构的变化尽管有心理社会干预，怀孕期间大量饮酒仍在继续成为西开普省、美国和全世界的一个重大公共卫生挑战。在最近的一项初步研究中，我们发现，在怀孕期间补充高剂量的母体胆碱可以减轻 PAE对婴儿生长和认知发育以及新生儿大脑结构的影响。这项建议将增加最近NIH资助的一项完全有效的双盲随机安慰剂对照试验中，288例重度饮用西开普省妇女将给予胆碱或安慰剂在怀孕期间和婴儿将进行评估直到12个月大我们建议增加新生儿神经影像学，包括脑解剖，扩散和代谢光谱成像，检查神经机制介导的有益效果，母亲补充胆碱对婴儿发育结果的影响。我们假设胆碱重度饮酒孕妇的补充剂将减少PAE对发育中通过正常化解剖发育，连接和大脑能量代谢来改善胎儿大脑。大脑发育需要能量，对营养储备高度敏感。酒精可测量会破坏大脑代谢物胆碱是乙酰胆碱的前体，乙酰胆碱是健康细胞中的关键代谢物发展胆碱储备的消耗加上酒精引起的破坏对胎儿产生不利影响大脑发育我们初步的婴儿大脑解剖数据显示，PAE对发育有明显的影响，母亲补充胆碱的缓解作用。我们将联合收割机结合临床和营养信息和婴儿认知测试结果从临床试验与大脑解剖，连接和代谢测量从目前的研究，以增加我们的理解的机制，产前母体胆碱补充剂对发育中胎儿的神经保护作用的基础在PAE的情况下的胎儿。我们将开发利用磁共振成像技术获取特定区域神经代谢信息的能力。共振光谱成像（MRSI）和深度学习来识别新生儿大脑区域。这个项目建立在Meintjes博士（开普敦大学），S。和j. 雅各布森（韦恩州立大学医学院）、货车德尔库韦（马萨诸塞州总医院）和卡特（哥伦比亚大学）。蔡博士和李博士，测量指定大脑能量代谢的专家使用MRSI的地区将担任这项研究的顾问。