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（由适用提供）：阿尔茨海默氏病（AD）的预防试验需要开发生物学标记，以识别出下降风险增加的正常（NL）个体。年龄后，具有一级家族史（FH）的后期广告是NL之间发展AD的最重要危险因素，尤其是在父母受到影响的情况下。尚不清楚AD供应后代风险的生物学机制。使用2- [18F]氟-2-脱氧-D-葡萄糖作为示踪剂（FDG-PET）的正电子发射断层扫描成像，我们证明，NL与AD（FHM）的主要历史（FHM）相比，与pertalal-aD（FHP相比）（FHP）（FHP）（FHP）（FHP）（FHP）（FHP）均显示出降低的AD（FHM）（FHM）（FHM）。 FHM中的CMRGLC降低涉及临床AD患者通常是低代谢的相同大脑区域。此外，与FHP和FH-相比，NL FHM在AD区显示CMRGLC的速率明显更高。我们先前的工作表明，CMRGLC减少发生在AD的临床前阶段，并预测NL认知到AD的下降。鉴于有关葡萄糖代谢涉及的分子过程和AD的病理生物生物学的所有已知性，NL FHM中的低代谢可能是由于线粒体增加氧化应激和淀粉样蛋白β（a。）沉积的组合，这被许多AD中的关键病理事件所认为。线粒体DNA仅在人类中遗传的事实向这一假设提供了支持。 - 相关的氧化应激可能在AD中CMRGLC异常的主动性和进展中起着至关重要的作用，而CMRGLC异常则使突触更容易受到神经变性的影响。这项研究的目的是检查CMRGLC，A e病理学和氧化应激之间的关系。我们建议对96岁25-50岁的NL进行为期3年的纵向研究，分为4个n = 24个受试者的FH组：FH-，FHM，FHP，AD（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和淀粉样蛋白PET（PIB-PET）检查。我们的第一个目的是检查NL FHM是否显示出CMRGLC减少，烟值增加以及氧化应激增加与FH-和FHP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，并具有足够的假设检验功率。 公共卫生相关性：阿尔茨海默氏病的初级预防试验将需要准确地鉴定出认知能力下降风险增加的正常人。我们表明，受广告影响的母亲的儿童在可膨胀区域显示出脑葡萄糖代谢减少，这可能会导致风险增加。该项目将检验以下假设：Ad-Moshers儿童的缺乏代谢是由于线粒体系统增加的氧化应激和淀粉样蛋白β的沉积增加所致。