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

基本信息

批准号：
10449489
负责人：
Bart Larsen
金额：
$ 10.99万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449489
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 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 Mediating Medical Records Mental disorders Mentorship Modeling Nutrient Outcome Parietal 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 Youth age related aged base brain abnormalities brain dysfunction 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 statistics translational model

项目摘要

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种多方面的结构，包括高阶认知过程，例如响应抑制，工作记忆和目标选择。行政能力在整个青春期都提高，并且执行功能或执行功能障碍的缺陷是许多精神病学的经诊断特征在这一发展时期出现的疾病。了解基础神经发育导致执行功能障碍的机制是目标干预措施的关键先决条件。铁缺乏症是世界上最常见的营养不足，是执行功能障碍的已知来源在童年和青春期的脆弱窗户中。然而，尽管率很高，并且影响，尚未完全了解潜在的神经生物学机制。该提议重点是将铁缺乏症与转诊高管联系起来的潜在至关重要但爆炸不足的机制功能障碍：脑铁缺乏症。 AIM 1将定义青春期脑铁缺乏症如何介导外周铁缺乏对执行功能障碍的影响。我们将首先研究这种关系基于社区的样本（n = 9,500，具有外围铁和认知评估，n = 1,601具有神经影像学）然后复制并将模型扩展到对精神疾病患者丰富的样本。 AIM 2将使用有或没有铁缺乏史的前瞻性收集的青少年样本年龄9-18蒙蒙的常规筛查，以确定童年和青春期的铁缺乏症如何影响脑铁缺乏症和青春期执行功能障碍。至关重要的是，这个目标将为多次打击在整个儿童期和青春期中的铁缺乏症的模型将与更大的脑铁有关缺乏症，因此比仅在两次中的铁缺乏症的执行功能更严重时期。最后，AIM 3将研究周围铁缺乏的性别差异如何影响性别差异青春期发作后的脑铁。这些目标共同确定了脆弱性的时机和执行功能障碍的神经生物学机制，从而为有针对性的转化模型提供了信息治疗和干预措施。该K99/R00独立奖的支持将提供申请人接受实现这些目标所需的培训，包括开发培训神经精神病学，认知评估，定量磁共振成像和晚期生物统计学。这些培训目标将在杰出的指导团队Drs的支持下实现。 Satterthwaite，Gur，Witschey，Shinohara，Wehrli和Georgieff，以及世界一流的技术和知识分子宾夕法尼亚大学的资源。拟议的科学目的和培训目标将在一起构成旨在发现神经发育的独立研究计划的基础患有精神疾病青年的执行功能障碍的机制。