Maternal history of Alzheimer's predisposes children to amyloid beta-related hypo

母亲患有阿尔茨海默病史使儿童容易患淀粉样蛋白β相关性低下症

• 批准号: 8127753
• 负责人: MONY J. de LEON
• 金额: $ 56.66万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127753
• 关键词: Accounting; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Asses; Biological; Biological Markers; Biological Markers; Blood; Blood Tests; Brain; Brain imaging; Brain region; Cerebrum; Child; Clinical; Cognition; Data; Dementia; Deoxyglucose; Deposition; Development; Elderly; Electron Transport; Energy Metabolism; Enzymes; Evaluation; Event; Family; Family history of; Fathers; Functional disorder; Genetic; Glucose; Goals; Human; Image; Impaired cognition; Individual; Inherited; Laboratories; Late Onset Alzheimer Disease; Longitudinal Studies; Magnetic Resonance Imaging; Mediating; Metabolic; Mitochondria; Mitochondrial DNA; Molecular; Mothers; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidative Stress; Parents; Pathology; Patients; Plasma; Play; Positron-Emission Tomography; Prevention; Primary Prevention; Procedures; Process; Production; Protocols documentation; Publishing; Quality Control; Reactive Oxygen Species; Recording of previous events; Reliance; Risk; Risk Factors; Role; Staging; Synapses; Testing; Tracer; Work; age related; base; cell type; cognitive function; early onset; follow-up; glucose metabolism; high risk; improved; in vivo; mitochondrial dysfunction; neuropsychological; offspring; oxidative damage; pre-clinical; public health relevance; transmission process

DESCRIPTION (provided by applicant): Prevention trials for Alzheimer's disease (AD) require development of biological markers to identify normal (NL) individuals at increased risk for decline. After age, having a 1st degree family history (FH) of late-onset AD is the most significant risk factor for developing AD among NL, especially when a parent is affected. The biological mechanisms through which a parental FH of AD confers risk to the offspring are not known. Using Positron Emission Tomography imaging with 2-[18F]fluoro-2-Deoxy-D-glucose as the tracer (FDG-PET), we demonstrated that NL elderly with a maternal history of AD (FHm) show reductions in the cerebral metabolic rate of glucose (CMRglc) as compared to those with a paternal history of AD (FHp) and those with a negative FH (FH-). CMRglc reductions in FHm involved the same brain regions that are typically hypometabolic in clinical AD patients. Moreover, NL FHm showed significantly higher rates of CMRglc declines in AD regions as compared to FHp and FH-. Our prior work demonstrates that CMRglc reductions occur at the preclinical stages of AD and predict decline from NL cognition to AD. With all that is known about the molecular processes involved in glucose metabolism and the pathophysiology of AD, hypometabolism in NL FHm may be due to a combination of increased oxidative stress from the mitochondria and increased amyloid beta (A¿) deposition, which is considered by many the key pathological event in AD. The fact that mitochondrial DNA is exclusively maternally inherited in humans lends support to this hypothesis. A¿-related oxidative stress may play a crucial role in the initiation and progression of CMRglc abnormalities in AD, which in turn render synapses more vulnerable to neurodegeneration. The goal of this study is to examine the relationship between CMRglc, A¿ pathology, and oxidative stress in young NL individuals at risk for AD. We propose to perform a 3-year longitudinal study of ninety-six 25-50 year old NL, divided into 4 FH groups of n=24 subjects each: FH-, FHm, FHp, maternal and paternal FH of AD (FHmp). All subjects will receive clinical, neuropsychological, blood tests, brain MRI, FDG-PET and amyloid-PET (PIB-PET) exams at baseline and follow-up. Our first aim will be to examine whether NL FHm show reduced CMRglc, increased Ass deposition and increased oxidative stress vs FH- and FHp, and whether the changes in these variables are related. Our second aim will be to examine whether FHmp show cross-sectional and longitudinal effects comparable to FHm. We will use standardized and quality controlled protocols and there is adequate power for hypothesis testing. PUBLIC HEALTH RELEVANCE: Primary prevention trials for Alzheimer's disease will require accurate identification of normal individuals at increased risk for cognitive decline. We showed that children of AD-affected mothers show reduced brain glucose metabolism in AD-vulnerable regions, which may account for the increased risk. This project will test the hypothesis that hypometabolism in children of AD-mothers is due to a combination of systemically increased oxidative stress from the mitochondria and increasing amyloid-beta deposition.

描述（由申请人提供）：阿尔茨海默病（AD）的预防试验需要开发生物标志物来识别衰退风险增加的正常（NL）个体。年龄后，迟发性AD的一级家族史（FH）是NL中发生AD的最重要危险因素，特别是当父母一方受到影响时。父母的阿尔茨海默病FH给后代带来风险的生物学机制尚不清楚。利用2-[18F]氟-2-脱氧- d -葡萄糖为示踪剂的正电子发射断层成像（FDG-PET），我们发现与父亲有AD病史（FHp）和FH阴性（FH-）的老年人相比，母亲有AD病史（FHm）的NL老年人的脑葡萄糖代谢率（CMRglc）降低。FHm的CMRglc减少涉及临床AD患者典型低代谢的相同大脑区域。此外，与FHp和FH-相比，NL FHm在AD区域的CMRglc下降率明显更高。我们之前的工作表明，CMRglc减少发生在阿尔茨海默病的临床前阶段，并预测了从NL认知到阿尔茨海默病的下降。根据已知的葡萄糖代谢和AD病理生理的分子过程，NL FHm的低代谢可能是由于线粒体氧化应激增加和淀粉样蛋白沉积增加的组合，这被许多人认为是AD的关键病理事件。人类线粒体DNA完全由母系遗传的事实支持了这一假设。与氧化应激相关的应激可能在阿尔茨海默病CMRglc异常的发生和发展中起着至关重要的作用，而CMRglc异常反过来又使突触更容易受到神经变性的影响。本研究的目的是研究有AD风险的年轻NL个体的CMRglc、A¿病理和氧化应激之间的关系。我们拟对96例25-50岁的NL患者进行为期3年的纵向研究，将其分为4组，每组n=24人：FH-、FHm、FHp、AD的母亲和父亲FH （FHmp）。所有受试者将在基线和随访时接受临床、神经心理学、血液检查、脑MRI、FDG-PET和PIB-PET检查。我们的第一个目标是检查NL FHm是否表现出与FH-和FHp相比CMRglc降低、Ass沉积增加和氧化应激增加，以及这些变量的变化是否相关。我们的第二个目标是检验FHmp是否表现出与FHm相当的横截面和纵向效应。我们将使用标准化和质量控制的方案，并有足够的权力进行假设检验。