Metabolic and physiological biomarkers for early detection of women at risk for A

用于早期检测有 A 风险的女性的代谢和生理生物标志物

• 批准号: 8669707
• 负责人: Jamaica Rettberg
• 金额: $ 2.37万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2014-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669707
• 关键词: Affect; Aging; Algorithms; Alzheimer' s Disease; American; Analysis of Covariance; Analysis of Variance; Basic Science; Bioenergetics; Biological Markers; Blood Pressure; Brain; Clinical; Clinical assessments; Cluster Analysis; Cognition; Cognitive; Collaborations; Collection; Complex; Data; Dementia; Development; Diagnosis; Disease; Early Diagnosis; Enrollment; Epidemiology; Estradiol; Estrogens; Evaluation; Female; Foundations; Functional disorder; Goals; High Prevalence; Impaired cognition; Individual; Intervention; Intervention Trial; Investigation; Late Onset Alzheimer Disease; Lead; Life; Linear Models; Linear Regressions; Lipids; Longevity; Measurement; Measures; Menopause; Metabolic; Metabolism; Modeling; Neurodegenerative Disorders; Nurses; Oral; Ovarian hormone; Performance; Peripheral; Phenotype; Physiological; Placebos; Plasma; Population; Process; Progesterone; Public Health; Randomized; Regression Analysis; Research; Research Personnel; Research Project Grants; Research Proposals; Risk; Sampling; System; Testing; Therapeutic; Time; Training; Translational Research; Visit; Woman; Women' s Group; base; bench to bedside; brain metabolism; clinical Diagnosis; clinically relevant; cognitive change; cognitive function; cohort; hormone therapy; pre-clinical; progressive neurodegeneration; public health relevance; repository; reproductive; response; senescence

DESCRIPTION (provided by applicant): Alzheimer's disease is a progressive, fatal neurodegenerative disorder for which there is no preventative treatment or cure. Over 5 million Americans are currently living with sporadic late-onset Alzheimer's disease; of those diagnosed, 65% are women. While the higher prevalence of women with Alzheimer's is in part due to greater lifespan, there is evidence that for some women the menopausal transition can initiate a process of accelerated aging, characterized by metabolic dysfunction and cognitive decline. Substantial basic discovery research demonstrates that the aging female brain undergoes profound shifts in metabolic capacity and function during the transition leading to reproductive senescence. Proposed herein is a translational research project that builds on this basic discovery research, and aims to elucidate the relationship between whole-body metabolic biomarkers and cognition in a population of menopausal women. For this project, our research group has assembled a repository of longitudinal clinical assessments and biospecimens collected from 643 women in the Early Versus Late Intervention Trial with Estradiol (R01AG-024154). The central hypothesis of this research proposal is that metabolic phenotypes will emerge following the menopausal transition; a subset of these phenotypes will be associated with a decline in cognitive performance, indicative of an at-risk phenotype of sporadic Alzheimer's disease. To test this hypothesis, two specific aims are proposed. The first aim is to develop a panel of metabolic biomarkers at baseline (pre- randomization) and to characterize their association with baseline cognitive function, prior to diagnosis of metabolic or cognitive dysfunction. The second aim builds on this metabolic foundation to specifically determine the trajectories of metabolic phenotypes and cognitive performance over a five-year period, with additional evaluation as to whether these associations are modified by randomization to menopausal hormone therapy. To accomplish these aims, statistical analysis ranging from simple ANOVA/ANCOVA analyses to complex mixed linear effects modeling and K-means cluster analysis will be employed. Completion of the proposed project will require collaboration with a diverse team of clinicians, researchers, nurses, and biostatisticians. Consequently, this research proposal will provide a unique training opportunity in clinical translational "bench to bedside" research. As Alzheimer's-related changes in the brain are known to begin years or decades before clinically detectable dementia, identification of biomarkers indicating the earliest preclinical changes is increasingly important. By using a systems-level approach, this research project seeks to develop a plasma-based biomarker panel to enable an affordable, rapidly deployable, and clinically relevant strategy to reliably detect an at-risk phenotype of sporadic AD.

描述（由申请人提供）：阿尔茨海默氏病是一种进行性致命的神经退行性疾病，没有预防治疗或治愈。目前，超过500万美国人患有零星的晚期阿尔茨海默氏病。在被诊断的人中，有65％是女性。尽管阿尔茨海默氏症患者的较高患病率较高，部分原因是寿命更高，但有证据表明，对于某些女性，绝经期过渡可以引发加速衰老的过程，其特征是代谢功能障碍和认知能力下降。实质性的基本发现研究表明，衰老的女性大脑在过渡过程中发生了代谢能力和功能的深刻变化，从而导致生殖衰老。本文提出的是一个基于这项基本发现研究的转化研究项目，旨在阐明全身代谢生物标志物与绝经妇女人群中的认知之间的关系。对于这个项目，我们的研究小组在早期与雌二醇（R01AG-024154）的早期与晚期干预试验中收集了从643名妇女收集的纵向临床评估和生物测量的存储库。 这项研究提案的中心假设是，在更年期过渡后将出现代谢表型。这些表型的一个子集将与认知表现的下降有关，这表明零星阿尔茨海默氏病的处于危险的表型。为了检验这一假设，提出了两个具体目标。第一个目的是在基线（前随机化）时开发一组代谢生物标志物，并在诊断代谢或认知功能障碍之前表征它们与基线认知功能的关联。第二个目标是基于这个代谢基础，以在五年内特异性确定代谢表型和认知表现的轨迹，并进行了其他评估，即这些关联是否通过随机与绝经激素治疗进行了改变。为了实现这些目标，将采用从简单的ANOVA/ANCOVA分析到复杂的混合线性效应建模和K-均值聚类分析的统计分析。拟议项目的完成将需要与临床医生，研究人员，护士和生物统计学家组成的多元化团队合作。因此，该研究建议将在临床翻译“卧床床位”研究中提供独特的培训机会。由于已知大脑中与阿尔茨海默氏症相关的变化是在临床可检测到的痴呆之前几年或数十年的，因此对生物标志物的鉴定表明最早 临床前的变化越来越重要。通过使用系统级方法，该研究项目试图开发基于等离子体的生物标志物面板，以实现负担得起的，可快速可部署和临床相关的策略，以可靠地检测出零星AD的高风险表型。