Characterizing the FASD cerebral cortex in utero with DTI

描述（由申请人提供）：胎儿暴露于酒精会导致广泛的神经功能缺陷，统称为胎儿酒精谱系障碍（FASD）。疾病预防控制中心估计，目前在美国，每1000个新生儿中就有4.5个患有FASD。如果在尽可能早的年龄开始，现有的干预策略可以改善受影响个体的生活质量。不幸的是，FASD的早期诊断是困难的，部分原因是这种疾病的行为表现直到儿童时期才明显。我们建议发展一种基于磁共振成像（MRI）的策略来检测发育中的大脑皮层中细胞水平的形态学改变。非人灵长类动物研究对象将被训练饮用1.5 g/kg/天的乙醇，或等热量的麦芽糖/糊精溶液。动物在怀孕的前60天将继续喝水，之后将停止使用乙醇。将采集3组乙醇或麦芽糖/糊精动物的胎儿脑t2加权和弥散张量成像（DTI）数据：1组在妊娠第85天(G)扫描，2组在妊娠第110天扫描，3组在妊娠第135天扫描。MRI后，胎儿将立即通过剖宫产娩出，并准备大脑进行组织学处理。本实验的第一个目的是表征早期乙醇暴露对G85至G135期间大脑皮质厚度、表面积和水扩散各向异性的影响。第二个目的是利用无偏体视技术验证乙醇暴露对皮质厚度的影响，并表征神经成像观察的生物来源。后者将通过测定大脑皮层细胞数量，测量神经细胞的体积分数，量化皮层神经元轴突和树突乔木的形态复杂性来完成。这项工作将为描述早期乙醇暴露对大脑皮层后续发育的影响提供一个客观的策略，这将有助于目前可以实现的FASD的早期检测。

DESCRIPTION (provided by applicant): Fetal exposure to alcohol leads to a wide range of neurological deficits collectively termed fetal alcohol spectrum disorders (FASD). The CDC estimates that FASD currently affects as many as 4.5 out of every 1000 births within the United States. Existing intervention strategies can improve the quality of life in affected individuals, provided they are initiated at the earliest age possible. Unfortunately, early FASD diagnosis is difficult, partly because behavioral manifestations of the disorder are not apparent until childhood. We propose to develop a magnetic resonance imaging (MRI)-based strategy to detect cellular-level morphological alterations in the developing cerebral cortex. Nonhuman primate research subjects will be bred after being trained to drink 1.5 g/kg/day of ethanol, or an isocaloric amount of maltose/dextrin solution. Animals will continue to drink throughout the first 60 days of pregnancy, after which access to ethanol will be terminated. Fetal brain T2-weighted and diffusion tensor imaging (DTI) data will be acquired on 3 groups of ethanol or maltose/dextrin animals: group 1 will be scanned on gestational day (G)85, group 2 on G110, and group 3 on G135. Immediately after MRI, fetuses will be delivered by cesarian section and brains will be prepared for histological processing. The first aim for this experiment is to characterize the effects of early ethanol exposure on cerebral cortical thickness, surface area, and water diffusion anisotropy over the period ranging from G85 to G135. The second aim is to validate the cortical thickness effects of ethanol exposure using unbiased stereological techniques, and to characterize the biological source of the neuroimaging observations. The latter will be accomplished by determining cerebral cortical cell numbers, measuring the volume fraction of the neuropil, and quantifying morphological complexity of cortical neuronal axonal and dendritic arbors. This work will provide an objective strategy for characterizing the effects o early ethanol exposure on subsequent development of the cerebral cortex, which will facilitate earlier detection of FASD that is currently achievable.