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

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，以识别下降风险增加的正常（NL）个体。年龄之后，具有迟发性AD的一级家族史（FH）是NL中发展AD的最重要风险因素，特别是当父母受到影响时。AD的亲代FH给后代带来风险的生物学机制尚不清楚。 使用正电子发射断层扫描成像与2-[18 F]氟-2-脱氧-D-葡萄糖作为示踪剂（FDG-PET），我们证明，NL老年人与AD（FHm）的母亲的历史显示降低脑葡萄糖代谢率（CMRglc）相比，与父亲的AD（FHp）和那些与一个负FH（FH-）。FHm的CMRglc降低涉及临床AD患者中通常代谢低下的相同脑区域。此外，NL FHm在AD区域中显示出比FHp和FH-显著更高的CMRglc下降率。我们先前的工作表明，CMRglc减少发生在AD的临床前阶段，并预测从NL认知到AD的下降。根据所有关于参与葡萄糖代谢的分子过程和AD的病理生理学的已知信息，NL FHm中的低代谢可能是由于线粒体氧化应激增加和淀粉样蛋白β（A？）沉积增加的组合，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这一事实支持了这一假设。A？- 相关的氧化应激可能在AD中CMRglc异常的启动和进展中起关键作用，这反过来使突触更容易受到神经变性的影响。 本研究的目的是研究在年轻的NL个体中，有AD风险的CMRglc、A？病理学和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n=24例受试者：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和淀粉样蛋白-PET（PIB-PET）检查。我们的第一个目标将是检查NL FHm是否显示降低的CMRglc，增加的Ass沉积和增加的氧化应激与FH-和FHp相比，以及这些变量的变化是否相关。我们的第二个目标将是检查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，并有足够的能力进行假设检验。 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个体。我们发现，受AD影响的母亲的孩子在AD易感区域表现出大脑葡萄糖代谢降低，这可能是导致风险增加的原因。该项目将测试AD母亲的儿童代谢低下是由于线粒体的全身性氧化应激增加和淀粉样蛋白β沉积增加的组合的假设。

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.