Neurodevelopment in children from families with genetic frontotemporal dementia and Alzheimer’s disease

遗传性额颞叶痴呆和阿尔茨海默病家族儿童的神经发育

• 批准号: 10571880
• 负责人: SUZEE EURIE LEE
• 金额: $ 78.03万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571880
• 关键词: Adult; Age; Alzheimer' s Disease; Amygdaloid structure; Animal Model; Attention; Attention deficit hyperactivity disorder; Behavioral Symptoms; Bilateral; Biological Markers; Biology; Brain; Child; Clinical; Cognitive; Corpus striatum structure; Cross-Sectional Studies; DNA Sequence Alteration; Data; Differential Diagnosis; Disease; Dominant Genes; Dyslexia; Early identification; Family; Family member; Frontotemporal Dementia; Functional Magnetic Resonance Imaging; Genetic; Human; Inferior; Insula of Reil; Language; Learning Disabilities; Left; Life; Longevity; Memory; Modeling; Mutation; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurodevelopmental Disorder; Pattern; Performance; Phase; Play; Primary Progressive Aphasia; Resources; Role; Structure; Symptoms; Syndrome; Work; aged; autism spectrum disorder; autistic children; autosome; behavior measurement; behavioral variant frontotemporal dementia; comparison control; disease-causing mutation; early detection biomarkers; executive function; frontal lobe; gray matter; insight; mutation carrier; neural circuit; neural network; neurodevelopment; neuroimaging; presenilin-1; white matter; young adult

PROJECT SUMMARY/ABSTRACT The current conceptualization of genetic frontotemporal dementia (FTD) and Alzheimer's disease (AD) is that they are neurodegenerative diseases with symptoms developing later in life. Yet, studies in animal models support the notion that autosomal dominant genes whose mutations cause these diseases play critical roles in neurodevelopment. Previous studies show that young adult presymptomatic carriers for FTD and AD mutations show detectable differences in the neural circuits that are also targeted during the symptomatic phase. It remains unknown how early these abnormalities start and the extent to which children with these mutations may show clinical overlap with neurodevelopmental disorders such as autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and language-based learning disabilities (LBLD). Studying children with FTD and AD mutations offers a unique model to evaluate lifelong neural circuit vulnerability since each disease targets distinct neural circuits. At the UCSF Dyslexia Center, we will cross-sectionally study children from families with a known genetic mutation for FTD or AD and compare them children with ASD, ADHD, and LBLD. Aims 1 and 2 will compare children carrying a genetic mutation for FTD and children carrying a genetic mutation for AD with noncarrier family members to identify differences in brain structure and neural network connectivity. Aim 3 will explore comparisons between mutation carriers and children with ASD, ADHD, and LBLD. Upon completion, we will have identified how early disease-specific neural circuit differences arise in genetic FTD and AD. These findings will reveal important insights into the underlying biology of these diseases and when biomarker differences develop during the lifespan for genetic FTD and AD.

项目概要/摘要 目前对遗传性额颞叶痴呆（FTD）和阿尔茨海默病（AD）的概念是： 它们是神经退行性疾病，症状在以后的生活中出现。然而，动物模型研究 支持以下观点：其突变导致这些疾病的常染色体显性基因在 神经发育。先前的研究表明，年轻成人症状前携带 FTD 和 AD 突变 显示出在症状阶段也是目标的神经回路中可检测到的差异。它 目前尚不清楚这些异常何时开始以及携带这些突变的儿童的程度 可能表现出与自闭症谱系障碍（ASD）等神经发育障碍的临床重叠， 注意力缺陷多动障碍（ADHD）和语言学习障碍（LBLD）。学习中 患有 FTD 和 AD 突变的儿童提供了一个独特的模型来评估终生神经回路脆弱性 每种疾病都针对不同的神经回路。在加州大学旧金山分校阅读障碍中心，我们将进行横断面研究 来自已知患有 FTD 或 AD 基因突变的家庭的儿童，并将他们与患有自闭症谱系障碍 (ASD) 的儿童进行比较， ADHD 和 LBLD。目标 1 和 2 将比较携带 FTD 基因突变的儿童和儿童 与非携带者家庭成员携带 AD 基因突变，以识别大脑结构和 神经网络连接。目标 3 将探讨突变携带者和自闭症儿童之间的比较， ADHD 和 LBLD。完成后，我们将确定早期疾病特异性神经回路如何 FTD 和 AD 存在遗传差异。这些发现将揭示对潜在问题的重要见解 这些疾病的生物学特性，以及在遗传性 FTD 和 AD 的生命周期中何时出现生物标志物差异。