Altered Brain Structure and Function in Adolescents with Behaviorally Acquired HIV

行为感染艾滋病毒青少年的大脑结构和功能发生改变

• 批准号: 9203858
• 负责人: Jennifer L McGuire
• 金额: $ 18.09万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203858
• 关键词: 20 year old; Accounting; Address; Adherence; Adolescence; Adolescent; Adult; Affect; Age; Back; Biological Markers; Biological Neural Networks; Brain; Brain Injuries; CD4 Positive T Lymphocytes; Caring; Characteristics; Child; Childhood; Cognition; Cognitive; Complex; Corpus striatum structure; Country; Cross-Sectional Studies; Data; Data Set; Development; Developmental Process; Disease; Epidemic; Epidemiologist; Female; Financial compensation; Functional Magnetic Resonance Imaging; Future; Goals; Growth; Growth and Development function; HIV; HIV Infections; High Prevalence; Image; Impaired cognition; Impairment; Incidence; Infection; Intervention; K-Series Research Career Programs; Knowledge; Lateral; Lead; Learning; Literature; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Memory; Mentors; Mission; Morbidity - disease rate; Motor; National Institute of Neurological Disorders and Stroke; Neurologic; Neurologic Examination; Neurologist; Neuronal Injury; Neurons; Pathologic; Pathway interactions; Pattern; Pediatric Hospitals; Pennsylvania; Performance; Pharmaceutical Preparations; Philadelphia; Pilot Projects; Population; Prefrontal Cortex; Prevalence; Problem Solving; Recording of previous events; Regimen; Research; Risk Factors; Safe Sex; Self-control as a personality trait; Signal Transduction; Structure; Testing; Training; United States; Universities; Virus; Visit; Vulnerable Populations; Youth; antiretroviral therapy; base; cognitive function; cognitive process; cognitive rehabilitation; cognitive testing; cohort; executive function; frontal lobe; gray matter; immune function; improved; male; medication compliance; morphometry; mortality; neurodevelopment; neuroimaging; neuroinflammation; patient oriented; prevent; processing speed; racial and ethnic; sex; therapeutic target; transmission process; treatment strategy; viral resistance; 20 year old; Accounting; Address; Adherence; Adolescence; Adolescent; Adult; Affect; Age; Back; Biological Markers; Biological Neural Networks; Brain; Brain Injuries; CD4 Positive T Lymphocytes; Caring; Characteristics; Child; Childhood; Cognition; Cognitive; Complex; Corpus striatum structure; Country; Cross-Sectional Studies; Data; Data Set; Development; Developmental Process; Disease; Epidemic; Epidemiologist; Female; Financial compensation; Functional Magnetic Resonance Imaging; Future; Goals; Growth; Growth and Development function; HIV; HIV Infections; High Prevalence; Image; Impaired cognition; Impairment; Incidence; Infection; Intervention; K-Series Research Career Programs; Knowledge; Lateral; Lead; Learning; Literature; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Memory; Mentors; Mission; Morbidity - disease rate; Motor; National Institute of Neurological Disorders and Stroke; Neurologic; Neurologic Examination; Neurologist; Neuronal Injury; Neurons; Pathologic; Pathway interactions; Pattern; Pediatric Hospitals; Pennsylvania; Performance; Pharmaceutical Preparations; Philadelphia; Pilot Projects; Population; Prefrontal Cortex; Prevalence; Problem Solving; Recording of previous events; Regimen; Research; Risk Factors; Safe Sex; Self-control as a personality trait; Signal Transduction; Structure; Testing; Training; United States; Universities; Virus; Visit; Vulnerable Populations; Youth; antiretroviral therapy; base; cognitive function; cognitive process; cognitive rehabilitation; cognitive testing; cohort; executive function; frontal lobe; gray matter; immune function; improved; male; medication compliance; morphometry; mortality; neurodevelopment; neuroimaging; neuroinflammation; patient oriented; prevent; processing speed; racial and ethnic; sex; therapeutic target; transmission process; treatment strategy; viral resistance

PROJECT SUMMARY/ABSTRACT Behaviorally acquired HIV infection during adolescence occurs in the midst of key brain developmental processes such as frontal lobe neuronal pruning and network selection. While incident HIV cases declined by 19% in the U.S. over the last decade, there was an 87% increase in new infections among subsets of 13-24 year-old youth, who now account for 26% of all new HIV infections. Despite this profound shift in the domestic epidemic, we know little about the effects of acquired HIV at these ages on brain development. This application proposes a mentored patient-oriented career development award (K23) for Jennifer McGuire, MD, MSCE, a Child Neurologist and Epidemiologist at the Children's Hospital of Philadelphia and the University of Pennsylvania. Her long-term goal is to use computational neuroimaging metrics to identify biomarkers and evaluate therapeutic targets in HIV and other virally-mediated neuroinflammatory disorders. These markers will be used to test hypotheses regarding specific pathologic mechanisms and potential interventions to limit brain damage. The objective of this proposal is to train Dr. McGuire in the planning, use, and analysis of structural and functional neuroimaging measurements correlated with cognitive assessments as a cross-sectional window into the effects of HIV on the developing brain. The central hypothesis, supported by related pilot data, is that HIV infection during adolescence has a particularly deleterious effect on vulnerable actively maturing neural networks. As such, this study hypothesizes that fronto-striatal pathways subserving executive function will be profoundly negatively impacted functionally and as evidenced by reduced striatal volumes. Specific aims are therefore to: 1. Define the overall prevalence and subdomain patterns of cognitive impairment in youth with behaviorally acquired HIV compared to controls using validated cognitive tests. 2. Determine the difference in striatal volumes in HIV+ youth (with and without cognitive impairment) and controls using MRI structural morphometry. 3. Quantify fronto-striatal activation signal as a measure of functional circuitry in HIV+ youth (with and without cognitive impairment) and controls using functional MRI (fMRI) activation signal during an executive function task (N-back). The proposed research will be performed in a cross-sectional study of 16-20 year old male and female Philadelphia youth of all racial and ethnic backgrounds with behaviorally acquired HIV (n=40) compared to age/sex/demographic/risk factor-matched uninfected controls (n=30). Cognitive testing, structural MRI, and fMRI will be performed during a single study visit that will include complete medical and medication histories, neurologic examinations, and immune function assessment on all youth. The NINDS mission is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurologic disease. By developing reliable cognitive and imaging metrics of the effects of acquired HIV on the adolescent brain in this K23, in future R01 projects Dr. McGuire will: 1) follow this cohort longitudinally to determine how brain growth and cognition trajectories differ from age-expected growth and development; 2) determine if optimization of cART regimens is neuro-protective in this population; 3) develop testable mechanistic hypotheses based on these data to lead to future studies of adjunctive therapies (pharmacologic and/or cognitive rehabilitation/ enrichment) to maximize neurodevelopment in HIV and later in other neuroinflammatory disorders; and 4) examine if maximizing executive function in HIV+ youth improves medication adherence, retention in care, and safe sex practices, ultimately helping to prevent this growing group from becoming an ongoing reservoir of HIV transmission.

项目摘要/摘要 在青春期期间行为获得的HIV感染发生在关键的大脑发育中 额叶神经元修剪和网络选择等过程。而事件艾滋病毒案件被拒绝 在过去的十年中，美国有19％在美国，在13-24的子集中新感染增加了87％ 一岁的青年，现在占所有新艾滋病毒感染的26％。尽管国内发生了深刻的转变 流行病，我们对这些年龄在这些年龄中获得的HIV对脑发育的影响一无所知。 该申请建议为詹妮弗·麦圭尔（Jennifer McGuire）一个受过指导的注重患者职业发展奖（K23）， MD，MSCE，费城儿童医院的儿童神经科医生和流行病学家 宾夕法尼亚大学。她的长期目标是使用计算神经影像学指标来识别 生物标志物并评估HIV和其他病毒介导的神经炎症性疾病中的治疗靶标。 这些标记将用于检验有关特定病理机制和潜力的假设 干预措施以限制大脑损伤。该建议的目的是培训麦奎尔博士的计划，使用， 以及与认知评估相关的结构和功能神经影像学测量的分析 作为进入HIV对发育中大脑的影响的横截面窗口。中央假设，支持 通过相关的试点数据，青春期的艾滋病毒感染对脆弱的影响特别有害 积极成熟的神经网络。因此，这项研究假设额 - 纹状体途径在 执行功能将在功能上受到深远的负面影响，并通过减少的纹状体证明 卷。因此，具体目标是： 1。定义行为上年轻人认知障碍的总体患病率和亚域模式 与使用经过验证的认知测试对照组相比，获得的HIV获得了。 2。确定艾滋病毒+青年纹状体体积的差异（有和没有认知障碍）和 使用MRI结构形态测定法对照。 3。量化额 - 纹状体激活信号作为艾滋病毒+青年功能电路的量度（有和没有 认知障碍）和使用功能性MRI（fMRI）激活信号在执行期间进行对照 功能任务（n-back）。 拟议的研究将在16-20岁的男性和女性的横断面研究中进行 与行为获得艾滋病毒（n = 40）的所有种族和种族背景的费城青年相比 年龄/性别/人口/人口/风险因素匹配的未感染对照（n = 30）。认知测试，结构MRI和 FMRI将在一次研究访问中进行，其中包括完整的医疗和药物历史， 对所有青年的神经检查和免疫功能评估。 Ninds的使命是寻求有关大脑和神经系统的基本知识，并使用它 知识减轻神经系统疾病的负担。通过开发可靠的认知和成像指标 在此K23中，获得的HIV对青春期大脑的影响，在未来的R01项目中，McGuire博士将：1）关注 该队列纵向确定脑生长和认知轨迹与年龄预期的不同 增长与发展； 2）确定在该人群中的优化手推车方案是否具有神经保护作用； 3）基于这些数据制定可检验的机械假设，以导致未来的辅助研究 疗法（药理和/或认知康复/富集），以最大化艾滋病毒的神经发育 后来在其他神经炎性疾病中； 4）检查艾滋病毒+青年的执行功能是否最大化 改善药物依从性，保留护理和安全的性行为，最终有助于防止这种情况 成长中的群体成为持续的HIV传播库。