Brain iron as a neurodevelopmental mechanism for transdianostic executive dysfunction

脑铁作为跨神经执行功能障碍的神经发育机制

• 批准号: 10879318
• 负责人: Bart Larsen
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10879318
• 关键词: Adolescence; Adolescent; Affect; Age; Age Months; Attention deficit hyperactivity disorder; Automobile Driving; Award; Basal Ganglia; Biometry; Blood; Blood Tests; Brain; Brain Mapping; Characteristics; Child; Childhood; Clinical; Cognitive; Communities; Corpus striatum structure; Data; Data Set; Development; Diagnostic; Executive Dysfunction; Female; Foundations; Functional Magnetic Resonance Imaging; Goals; Gur; Hemoglobin; Image; Individual; Individual Differences; Intervention; Iron; Laboratories; Life; Link; MRI Scans; Magnetic Resonance Imaging; Maps; Mediating; Medical Records; Mental disorders; Mentorship; Modeling; Nutrient; Outcome; Pathologic; Pathway interactions; Pennsylvania; Peripheral; Phase; Philadelphia; Physiology; Predisposition; Prevalence; Psychoses; Puberty; Public Health; Recording of previous events; Research; Resolution; Sampling; Severity of illness; Sex Differences; Short-Term Memory; Societies; Source; Symptoms; T2 weighted imaging; Testing; Time; Training; University resources; Work; Youth; age related; aged; brain abnormalities; clinically relevant; cognitive process; cognitive testing; cohort; data resource; early adolescence; early childhood; executive function; improved; improved outcome; iron deficiency; male; neurobiological mechanism; neuroimaging; neuropsychiatry; neurotransmission; programs; prospective; recruit; response; routine screening; screening; screening guidelines; statistics; translational model

PROJECT ABSTRACT Executive function is a multifaceted construct that includes higher-order cognitive processes such as response inhibition, working memory, and goal selection. Executive abilities improve throughout adolescence, and deficits of executive function, or executive dysfunction, are a transdiagnostic feature of many psychiatric disorders that emerge during this period of development. Understanding the underlying neurodevelopmental mechanisms that contribute to executive dysfunction is a critical prerequisite for targeted interventions. Iron deficiency is the most common nutrient deficiency in the world and is a known source of executive dysfunction during the vulnerable windows of early childhood and adolescence. However, despite its prevalence and impact, the underlying neurobiological mechanisms are not fully understood. This proposal focuses on a potentially critical but under-explored mechanism linking iron deficiency to transdiagnostic executive dysfunction: brain iron deficiency. Aim 1 will define how brain iron deficiency during adolescence mediates the effect of peripheral iron deficiency on executive dysfunction. We will first investigate this relationship in a large community-based sample (n=9,500 with peripheral iron and cognitive assessment, n=1,601 with neuroimaging) and then replicate and extend the model to a sample that is enriched for individuals with psychiatric disorders. Aim 2 will use a prospectively collected sample of adolescents with and without a history of iron deficiency in routine screenings at 9-18monts of age to determine how iron deficiency across childhood and adolescence impacts brain iron deficiency and executive dysfunction in adolescence. Critically, this aim will inform a multi-hit model whereby iron deficiency across childhood and adolescence will be associated with greater brain iron deficiency and thus more severe executive function than having iron deficiency in only one of the two time periods. Finally, Aim 3 will examine how sex differences in peripheral iron deficiency impact sex differences in brain iron after the onset of puberty. Together, these aims will identify both the timing of vulnerability and the neurobiological mechanisms underlying executive dysfunction, thus informing translational models for targeted treatments and interventions. The support of this K99/R00 Pathway to Independence award will provide the applicant with the training necessary to achieve these aims, including training in developmental neuropsychiatry, cognitive assessment, quantitative magnetic resonance imaging, and advanced biostatistics. These training objectives will be accomplished with the support of an outstanding mentorship team, Drs. Satterthwaite, Gur, Witschey, Shinohara, Wehrli, and Georgieff, and the world class technical and intellectual resources of the University of Pennsylvania. Together, the proposed scientific aims and training objectives will form the foundation for an independent research program aimed at uncovering the neurodevelopmental mechanisms for executive dysfunction in youth with mental illness.

项目摘要 执行功能是一个多方面的结构，它包括更高阶的认知过程，如反应 抑制、工作记忆和目标选择。执行能力在整个青春期都有所提高，而且 执行功能缺陷，或执行功能障碍，是许多精神病患者的跨诊断特征 在这一发育阶段出现的紊乱。了解潜在的神经发育 导致执行功能障碍的机制是进行有针对性干预的关键前提。铁 营养缺乏症是世界上最常见的营养缺乏症，也是导致执行功能障碍的已知原因。 在儿童早期和青春期的脆弱时期。然而，尽管它的流行和 影响，其潜在的神经生物学机制尚不完全清楚。这项提案的重点是 潜在的关键但未被探索的将缺铁与跨诊断执行联系起来的机制 功能障碍：大脑缺铁。目标1将定义青春期大脑缺铁如何调节 外周缺铁对执行功能障碍的影响。我们将首先对这种关系进行大范围的调查 以社区为基础的样本(9,500人接受外周铁质和认知评估，1,601人接受神经成像) 然后将该模型复制并扩展到为患有精神障碍的个人丰富的样本。 Aim 2将使用前瞻性收集的有和没有缺铁病史的青少年样本 在9-18个月年龄进行常规筛查，以确定儿童和青春期缺铁 影响青春期大脑缺铁和执行功能障碍。最重要的是，这个目标会让你的多点命中 儿童和青春期缺铁与较高的脑铁含量相关的模型 缺铁，因此比两次中只有一次缺铁更严重的执行功能 句号。最后，目标3将检查外周缺铁的性别差异如何影响儿童的性别差异 青春期开始后的脑铁。综合起来，这些目标将确定脆弱性的时间和 执行功能障碍的神经生物学机制，从而为靶向翻译模型提供信息 治疗和干预。K99/R00独立之路奖的支持将提供 申请者接受实现这些目标所需的培训，包括发展方面的培训 神经精神病学、认知评估、定量磁共振成像和高级生物统计学。 这些培训目标将在一支出色的导师团队的支持下实现。 萨特斯韦特、古尔、维茨希、西野原、魏利、乔治耶夫，以及世界级的技术和知识分子 宾夕法尼亚大学的资源。综合起来，拟议的科学目标和培训目标将 为一个旨在揭示神经发育的独立研究计划奠定了基础 青少年精神病患者执行功能障碍的机制。