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）：阿尔茨海默病是一种进行性、致命的神经退行性疾病，目前尚无预防性治疗或治愈方法。目前，超过500万美国人患有散发性迟发性阿尔茨海默病，其中65%为女性。虽然阿尔茨海默氏症女性患病率较高的部分原因是寿命较长，但有证据表明，对于一些女性来说，更年期过渡可能会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。大量的基础发现研究表明，衰老的女性大脑在导致生殖衰老的过渡期间经历了代谢能力和功能的深刻变化。本文提出的是一个转化研究项目，该项目建立在这一基础发现研究的基础上，旨在阐明绝经期妇女群体中全身代谢生物标志物与认知之间的关系。对于这个项目，我们的研究小组已经收集了一个纵向临床评估和生物标本的资料库，这些资料库是从早期与晚期干预试验中的643名女性中收集的。 这项研究建议的中心假设是，代谢表型将出现绝经过渡后，这些表型的子集将与认知能力下降，指示散发性阿尔茨海默病的风险表型。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（随机化前）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其与基线认知功能的相关性。第二个目标建立在这个代谢基础上，专门确定五年内代谢表型和认知表现的轨迹，并额外评估这些相关性是否通过随机分配到绝经期激素治疗而改变。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模型和K均值聚类分析的统计分析。完成拟议的项目将需要与临床医生，研究人员，护士和生物统计学家的多元化团队合作。因此，这项研究提案将提供一个独特的培训机会，在临床翻译“板凳到床边”的研究。由于已知阿尔茨海默病相关的大脑变化在临床可检测的痴呆症之前开始数年或数十年， 临床前变化越来越重要。通过使用系统水平的方法，该研究项目旨在开发一种基于血浆的生物标志物面板，以实现经济实惠，快速部署和临床相关的策略，以可靠地检测散发性AD的风险表型。