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.

项目摘要/摘要 目前遗传性额颞叶痴呆(FTD)和阿尔茨海默病(AD)的概念是 它们是神经退行性疾病，症状会在生命的后期发展。然而，在动物模型中的研究 支持这样的观点，即常染色体显性基因的突变导致这些疾病在 神经发育。先前的研究表明，青年症状前FTD和AD突变携带者 显示神经回路中可检测到的差异，这些神经回路也是症状阶段的靶点。它 目前尚不清楚这些异常开始的时间有多早，以及携带这些突变的儿童 可能表现出与神经发育障碍如自闭症谱系障碍(ASD)的临床重叠， 注意力缺陷多动障碍(ADHD)和基于语言的学习障碍(LBLD)。学习 患有FTD和AD突变的儿童提供了一个独特的模型来评估终身神经回路易损性，因为 每种疾病都以不同的神经回路为目标。在加州大学旧金山分校的阅读障碍中心，我们将横断面研究 来自已知FTD或AD基因突变家庭的儿童，并将他们与ASD儿童进行比较， ADHD和LBLD。目标1和目标2将比较携带FTD基因突变的儿童和儿童 携带AD的基因突变与非携带者家庭成员，以确定大脑结构和 神经网络连接。目标3将探索突变携带者和ASD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 在遗传FTD和AD方面存在差异。这些发现将揭示对潜在的 这些疾病的生物学，以及在遗传性FTD和AD的生命周期中出现生物标志物差异的时间。