Identification of a non-invasive neuroimaging biomarker of prenatal synaptic development

产前突触发育的非侵入性神经影像生物标志物的鉴定

• 批准号: 9808337
• 负责人: Stephanie Mary Groman
• 金额: $ 20.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808337
• 关键词: Adolescence; Adult; Age-Months; Alzheimer' s Disease; Animal Model; Anisotropy; Autopsy; Behavior; Behavioral; Binding; Biological Markers; Birth; Brain; Child; Cognition; Cognitive; Conceptions; Data; Development; Diagnostic; Disease; Future; Glycoproteins; Goals; Human; Image; Imaging Techniques; Infant; Lead; Learning; Life; Link; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Mental Depression; Mental disorders; Monkeys; Neurons; Pathologic; Pathology; Pilot Projects; Positron-Emission Tomography; Pregnancy; Process; Proteins; Radiation; Reporting; Research Domain Criteria; Rewards; Scanning; Schizophrenia; Short-Term Memory; Specificity; Structure; Synapses; Synaptic Vesicles; Techniques; Thinness; Tissues; Tracer; Translating; Variant; Vesicle; Vulnerable Populations; autism spectrum disorder; base; brain behavior; brain morphology; cognitive development; cognitive process; cognitive testing; density; developmental disease; endophenotype; experimental study; fetal; gray matter; human subject; imaging properties; in utero; in vivo; innovation; insight; interest; magnetic resonance imaging biomarker; mental development; morphometry; myelination; neural circuit; neurodevelopment; neuroimaging marker; non-invasive imaging; nonhuman primate; noninvasive diagnosis; novel; postnatal; postnatal development; prenatal; psychologic; radioligand; relating to nervous system; response; synaptogenesis; tool; white matter

Project summary and abstract One of the most profound changes that occurs during gestational development is the rapid increase in the connections between neurons. Synaptogenesis, or the formation of synapses, that occurs in utero is critical for subsequent neural development, and several mental and developmental disorders are believed to be the resultant of alterations in prenatal synaptogenesis. Synaptic quantification, until recently, has required post- mortem tissue, so direct evidence linking prenatal synaptic disruptions with postnatal neural and behavioral development has been limited. We have recently developed a novel positron emission tomography (PET) radioligand ([11C]UCB-J) that targets synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in almost all synaptic vesicles, and have demonstrated that [11C]UCB-J is able to detect subtle alterations in human disorders, such as Alzheimer’s disease. We have conducted a pilot study using [11C]UCB-J to quantify synaptic development throughout prenatal and postnatal development in non-human primates and have found striking changes in [11C]UCB-J binding that parallel post-mortem measures of synaptogenesis. Therefore, longitudinally characterization of synaptic density with [11C]UCB-J has the potential to provide unprecedented insight into the developmental mechanisms that underlie mental illness. This proposal will use [11C]UCB-J to quantify synapses throughout gestation and the first nine postnatal months in non-human primates to determine the predictive relationship between prenatal synaptic development and postnatal development of the brain and cognition. In the first aim, we will quantify SV2A during gestation (post-conception days 120 and 150) and following birth (postnatal days 15, 30, 60, 120 and 240) to determine if development trajectories of SV2A co-vary with changes in reward learning, working memory and response inhibition, which are cognitive domains known to be altered in mental illness. The second aim will determine the relationship between prenatal SV2A density and magnetic resonance (MR) measures in order to identify a putative MR biomarker of prenatal synaptic density that could serve as a noninvasive diagnostic tool for use in human infants. Measures of brain morphometry, myelination and functional connectivity will be longitudinally assessed in the same infant non-human primates used in Aim 1 following birth (postnatal days 30, 60, 120 and 240) and related to synaptic and cognitive development trajectories of the same monkey. These studies of normal development in non- human primates will provide the preliminary data for future studies examining SV2A in animal models of mental illness, and ultimately lead to the identification of noninvasive MR imaging biomarker of prenatal synaptic density that can be safely acquired in human infants and children and serve as a diagnostic tool.

项目摘要和摘要 妊娠发展期间发生的最深刻的变化之一是迅速增加 神经元之间的连接。在子宫内发生的突触发生或突触的形成至关重要 随后的中立发展以及几种心理和发育障碍被认为是 产前突触发生改变的结果。直到最近，突触定量都需要 Mortem组织，因此直接证据将产前突触中断与产后神经和行为联系起来 开发是有限的。我们最近开发了一种新颖的正电子发射断层扫描（PET） 靶向合成囊泡糖蛋白2a（SV2A）的放射性基因（[11C] UCB-J），几乎所有蛋白 突触蔬菜，并证明[11C] UCB-J能够检测到人类的微妙变化 疾病，例如阿尔茨海默氏病。我们已经使用[11C] UCB-J进行了一项试点研究以量化突触 整个非人类隐私的产前和产后发展的发展，并发现了醒目 [11C] UCB-J结合的变化是平行的突触发生后测量。所以， [11C] UCB-J对突触密度的纵向表征有可能提供前所未有的 深入了解精神疾病基础的发展机制。该建议将使用[11C] UCB-J到 在整个妊娠中量化突触和非人类隐私的前九个月 确定产前突触发展与产后发展之间的预测关系 大脑和认知。在第一个目标中，我们将在妊娠期间量化SV2A（概念后第120天和150天） 出生后（产后第15、30、60、120和240天），以确定SV2A的发展轨迹是否存在 与奖励学习，工作记忆和响应抑制的变化，这是认知的 已知在精神疾病中改变的领域。第二个目标将决定 产前SV2A密度和磁共振（MR）措施，以识别推定的MR生物标志物 产前突触密度可以用作无创诊断工具用于人类婴儿。措施 将在同一婴儿中纵向评估脑形态计量学，髓鞘形成和功能连通性 出生后AIM 1中使用的非人类隐私（产后30、60、120和240），与突触有关 以及同一猴子的认知发展轨迹。这些关于非 - 非正常发展的研究 人类初选将为未来的研究提供初步数据，以研究心理动物模型中的SV2A 疾病，最终导致鉴定出产前突触的无创MR成像生物标志物 可以在人类和儿童中安全获得的密度，并用作诊断工具。