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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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目总结/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，这些疾病是神经退化性疾病，症状会在晚年出现。然而，动物模型的研究支持常染色体显性基因的突变导致这些疾病的概念，在神经发育先前的研究表明，年轻的前驱症状携带者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多早开始，以及这些突变的儿童在多大程度上可能显示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）和语言学习障碍（LBLD）。研究患有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的脆弱性，每种疾病针对不同的神经回路。在加州大学旧金山分校诵读困难中心，我们将进行横断面研究，来自具有已知FTD或AD基因突变的家庭的儿童，并将其与ASD儿童进行比较， ADHD和LBLD。目的1和2将比较携带FTD基因突变的儿童和携带AD基因突变的非携带者家庭成员，以确定大脑结构的差异，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，我们将确定如何早期疾病特异性神经回路在遗传FTD和AD中出现差异。这些发现将揭示重要的见解，这些疾病的生物学以及遗传性FTD和AD的生物标志物差异在寿命期间何时出现。