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

母亲患有阿尔茨海默氏病史使儿童容易患上淀粉样蛋白β相关的疾病

• 批准号: 7984348
• 负责人: MONY J. de LEON
• 金额: $ 60.78万
• 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/7984348
• 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 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; fluorodeoxyglucose positron emission tomography; 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记物来识别正常(NL)个体，这些个体具有更高的下降风险。在NL人群中，晚发性AD的一级家族史(FH)是NL人群中最显著的AD发病危险因素，尤其是在父母一方患病的情况下。阿尔茨海默病的亲本FH给后代带来风险的生物学机制尚不清楚。用2-[18F]氟-2-脱氧-D-葡萄糖作为示踪剂的正电子发射断层扫描(FDG-PET)显示，与父亲有AD病史(FHP)和FH阴性(FH-)相比，母亲有AD病史(FHM)的NL老年患者的大脑葡萄糖代谢率(CMRglc)降低。FHM中CMRglc的减少涉及到临床AD患者典型的低代谢脑区。此外，NL FHM在AD区域的CMRglc下降率明显高于FHP和FH-。我们先前的工作表明，CMRglc的降低发生在AD的临床前阶段，并预测从NL认知到AD的下降。随着对参与糖代谢的分子过程和AD的病理生理学的了解，NL FHM的低代谢可能是由于线粒体氧化应激增加和淀粉样β蛋白(A)沉积增加所致，这被许多人认为是AD的关键病理事件。线粒体DNA在人类中完全是母系遗传的事实支持了这一假说。与氧化应激相关的氧化应激可能在AD中CMRglc异常的启动和发展中发挥关键作用，而CMRglc异常反过来又使突触更容易受到神经退化的影响。这项研究的目的是检查CMRglc，A？病理，和有AD风险的年轻NL个体的氧化应激之间的关系。我们建议对96例25-50岁的NL进行为期3年的纵向研究，分为4个FH组，每组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、血液测试、脑MRI、FDG-PET和淀粉样PET(PIB-PET)检查。我们的第一个目标将是检查NL FHM是否表现出与FH-和FHP相比CMRglc减少，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查FHMP是否显示出与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。 公共卫生相关性：阿尔茨海默病的初级预防试验将需要准确识别认知能力下降风险增加的正常人。我们发现，受AD影响的母亲的孩子在易患AD的区域表现出大脑葡萄糖代谢降低，这可能是风险增加的原因。这个项目将检验这样一种假设，即AD母亲的孩子的低代谢是由于线粒体系统性氧化应激增加和淀粉样β蛋白沉积增加的组合。