Neuroimaging and Neurochemical Biomarkers in ADHD

ADHD 的神经影像和神经化学生物标志物

• 批准号: 7818322
• 负责人: JENNIFER G. LEVITT
• 金额: $ 49.93万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7818322
• 关键词: Adult; Advocate; Affect; Anisotropy; Anxiety; Attention deficit hyperactivity disorder; Behavioral; Biological; Biological Markers; Biology; Brain; Candidate Disease Gene; Child; Cognitive; Complex; Coupled; DRD4 gene; Data; Dependence; Diagnostic; Diffusion Magnetic Resonance Imaging; Dimensions; Disease; Disruptive Behavior Disorder; Early Diagnosis; Electroencephalography; Etiology; Family; Foundations; Future; Gene Expression; General Population; Genes; Genetic; Genetic Heterogeneity; Genotype; Goals; High Prevalence; Hyperactive behavior; Image; Impulsivity; Individual; Inferior; Intervention; Investigation; Link; Magnetic Resonance Imaging; Maps; Measures; Memory impairment; Mental disorders; Methods; Metric; Middle frontal gyrus structure; Mood Disorders; Morbidity - disease rate; Nature; Neurobiology; Neurocognitive; Neurodevelopmental Disorder; Parietal; Pathway interactions; Phenotype; Population; Population Study; Prefrontal Cortex; Prevalence; Protons; Radioactive; Reading Disabilities; Recruitment Activity; Recurrence; Research; Research Design; Risk; Sampling; Short-Term Memory; Siblings; Site; Societies; Symptoms; Techniques; Temperament; Testing; Thick; Time; Variant; Work; Youth; base; cingulate gyrus; cost; data integration; developmental disease; endophenotype; family genetics; genome-wide linkage; gray matter; improved; inattention; interest; magnetic resonance spectroscopic imaging; neurochemistry; neuroimaging; tool; white matter

DESCRIPTION (provided by applicant): Although ADHD represents one of the most common psychiatric disorders of youth, the biological underpinnings remain largely unknown. The prevalence of ADHD in the general population is estimated at 3- 9%, and the risk of recurrence in a sibling is increased 3-5 times that of siblings of healthy controls. The high prevalence rate coupled with the increased risk for several co-morbid conditions including reading disabilities (~20%), disruptive behavior disorders (~60%), anxiety/mood disorders (40%), and substance abuse/dependence (~40%) underscores the morbidity of this disorder and the potential costs to the individual and society. Symptom clusters of inattention and/or hyperactivity and impulsivity are diagnostic of the illness, but appear partially independent. Given the heterogeneous nature of ADHD, identification of biomarkers that are heritable phenotypes that more closely reflect gene expression (i.e., endophenotypes) is essential to further our understanding of the biology of this disorder. Recently, 'converging methods' approaches or 'multiple level of analysis' approaches are advocated in the investigation of complex neurodevelopmental disorders such as ADHD The availability of non-invasive, non-radioactive neuroimaging techniques and sophisticated data analytic approaches used in combination with neurophysiologic (EEG), neurocognitive and family genetic data holds the promise of greatly improving our ability to identify these biomarkers. The principal goal of the work proposed in this project is to use these tools to identify neuromorphometric and neurochemical measures that, in concert with electrophysiologic and neurocognitive measures, define meaningful endophenotypes in ADHD. In addition, the extent to which these measures are shared among siblings and therefore are familial will be explored as a means of identifying these endophenotypes. Using these tools, Sibling Pairs (30 pairs concordant and 30 pairs discordant for ADHD) selected from the ADHD Genetic Study (AGS) (Loo PI) at UCLA, and a sample of healthy control children will be examined. The AGS study population is a large group of multiplex families with phenotypic and genotype data available for access. We propose that key behavioral phenotypic dimensions of ADHD including: EEG metrics and working memory deficits are associated with specific brain neuromorphometric and neurochemical measures. Furthermore, we will examine the extent to which the neurobiologic findings underlying these phenotypic variations will be correlated among siblings, suggesting that they may be useful phenotypes for future investigations. Taken together, these studies will provide the basis for genetic studies to delineate specific gene > brain> behavioral pathways and lay the foundation for early detection and better intervention in ADHD. Although attention deficit/hyperactivity disorder affects a significant number of children and adults, and despite a great deal of research in this field, the underlying biology remains poorly understood. In this proposal, we plan to combine cutting edge neuroimaging techniques with electrophysiologic and neurocognitive measures, in order to delineate potential biomarkers of ADHD. The combination of these techniques will provide a powerful approach to unraveling this complex neurodevelopmental disorder.

描述（由申请人提供）： 尽管多动症是青少年最常见的精神疾病之一，但其生物学基础仍然很大程度上未知。一般人群中 ADHD 的患病率估计为 3-9%，兄弟姐妹复发的风险比健康对照的兄弟姐妹增加 3-5 倍。高患病率加上多种共病的风险增加，包括阅读障碍（~20%）、破坏性行为障碍（~60%）、焦虑/情绪障碍（40%）和药物滥用/依赖（~40） %) 强调了这种疾病的发病率以及对个人和社会的潜在成本。注意力不集中和/或多动和冲动的症状群可以诊断疾病，但似乎部分独立。鉴于 ADHD 的异质性，鉴定更能反映基因表达（即内表型）的可遗传表型生物标志物对于进一步了解这种疾病的生物学至关重要。最近，在复杂的神经发育障碍（例如多动症）的研究中提倡使用“融合方法”方法或“多层次分析”方法。非侵入性、非放射性神经影像技术和与神经生理学结合使用的复杂数据分析方法的可用性。脑电图）、神经认知和家族遗传数据有望大大提高我们识别这些生物标志物的能力。该项目提出的工作的主要目标是使用这些工具来识别神经形态测量和神经化学测量，这些测量与电生理和神经认知测量相结合，定义 ADHD 中有意义的内表型。此外，将探讨这些措施在兄弟姐妹之间共享并因此具有家族性的程度，作为识别这些内表型的一种手段。使用这些工具，将从加州大学洛杉矶分校 ADHD 遗传研究 (AGS) (Loo PI) 中选出的兄弟姐妹对（ADHD 的 30 对一致和 30 对不一致）以及健康对照儿童样本进行检查。 AGS 研究群体是一大群多重家族，具有可供访问的表型和基因型数据。我们提出 ADHD 的关键行为表型维度包括：脑电图指标和工作记忆缺陷与特定的大脑神经形态测量和神经化学测量相关。此外，我们将检查这些表型变异背后的神经生物学发现在兄弟姐妹之间的相关程度，表明它们可能是未来研究有用的表型。总而言之，这些研究将为遗传学研究提供基础，描绘特定的基因>大脑>行为途径，为ADHD的早期发现和更好的干预奠定基础。尽管注意力缺陷/多动症影响了大量的儿童和成人，并且尽管在该领域进行了大量研究，但其潜在的生物学仍然知之甚少。在这项提案中，我们计划将尖端的神经影像技术与电生理和神经认知测量相结合，以描绘 ADHD 的潜在生物标志物。这些技术的结合将为解决这种复杂的神经发育障碍提供一种强有力的方法。