Mechanisms and Predictors of Brain Aging in Healthy Aging, Preclinical AD and MCI

健康老龄化、临床前 AD 和 MCI 中脑衰老的机制和预测因子

• 批准号: 10404663
• 负责人: Karen M Rodrigue
• 金额: $ 66.6万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404663
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Axon; Basal Ganglia; Biological Markers; Brain; Cognition; Cognitive; Cognitive aging; Dementia; Dendrites; Deposition; Development; Diagnosis; Elderly; Functional Magnetic Resonance Imaging; Human; Image; Impaired cognition; Impairment; Individual; Inflammation; Investigation; Iron; Judgment; Link; MRI Scans; Measures; Molecular; Neurites; Neurocognitive; Neurocognitive Deficit; Pathologic; Pathology; Pattern; Process; Prospective Studies; Public Health; Reporting; Research; Research Design; Risk; Risk Factors; Senile Plaques; Signal Transduction; Synapses; Techniques; Testing; abeta accumulation; abeta deposition; age effect; age related; aging brain; animal model development; blood oxygen level dependent; blood oxygenation level dependent response; brain health; brain volume; cognitive performance; density; design; health goals; healthy aging; high risk; in vivo; indexing; insight; iron metabolism; middle age; mild cognitive impairment; multimodality; normal aging; novel; pathological aging; potential biomarker; pre-clinical; prospective; relating to nervous system; response

The distinction between healthy aging and pathology is imprecise and is clouded by overlap among normal brain aging markers and neural changes associated with Alzheimer’s disease (AD). Even in the case of beta-amyloid deposition, a key hallmark of AD, 20-30% of healthy older individuals show elevated amyloid, yet it remains unclear if these individuals will necessarily progress to dementia. Therefore, there is significant need for studies designed to investigate novel, lesser-studied mechanisms of brain aging, which may help disambiguate the neural changes that are early indicators of a pathological trajectory vs. signs of normal aging. The present study aims to provide new insight into neurocognitive aging with a multimodal investigation of important and understudied mechanisms of brain aging from molecular changes (iron accumulation and Aβ deposition) to synaptic changes (neurite complexity) to changes in brain function (BOLD modulation of activation) and their influence on cognition in middle-aged, older and MCI individuals. Critically, we propose to prospectively study healthy aging individuals who systematically vary in risk for AD (cognitively healthy low risk for AD, cognitively healthy elevated risk for AD) alongside individuals with Mild Cognitive Impairment (MCI), who are more likely to be in the early stages of neuropathological development. Through this approach, we aim to help elucidate some of the mechanisms underlying key aspects of brain and cognitive aging in healthy adults and also to distinguish which age-related brain changes may signal preclinical AD vs. non-pathological aging. The first aim proposes to examine brain iron accumulation as an early marker for cognitive and neural decline. We will study the impact of increased brain iron on cognitive performance and fMRI measured brain activation in healthy aging, preclinical AD and MCI. Secondly, we aim to examine the effect of synaptic complexity on cognitive performance and brain activation across risk groups. We will examine the relationship of both iron accumulation and synaptic complexity measures to beta-amyloid accumulation in preclinical aging and MCI to gauge whether these variables may serve as sensitive biomarkers for pathological aging. Finally, we plan to test the hypothesis that differences in neural modulation to cognitive difficulty as measured with fMRI may serve as a biomarker for preclinical AD. Completion of the current study is expected to advance understanding of the mechanisms and predictors of healthy brain aging versus a pathological aging trajectory.

健康衰老和病理性衰老之间的区别并不精确，并且因重叠而变得模糊 正常大脑衰老标志物和与阿尔茨海默病相关的神经变化 (AD) 即使在 β-淀粉样蛋白沉积（AD 的一个关键标志）的情况下，也有 20-30% 的健康人出现这种情况。 老年人的淀粉样蛋白水平升高，但尚不清楚这些人是否会 因此，非常需要开展旨在预防痴呆的研究。 研究新颖的、研究较少的大脑衰老机制，这可能有助于消除歧义 神经变化是病理轨迹与正常衰老迹象的早期指标。 本研究旨在通过多模式提供对神经认知衰老的新见解 从分子变化研究大脑衰老的重要和尚未研究的机制 （铁积累和 Aβ 沉积）到突触变化（神经突复杂性）到变化 脑功能（BOLD 激活调节）及其对中年认知的影响 重要的是，我们建议对健康的老龄个体进行前瞻性研究。 AD 风险存在系统性差异的人（认知健康 AD 风险低，认知健康 AD 风险升高）以及患有轻度认知障碍 (MCI) 的人 通过这种方法，我们可能处于神经病理学发展的早期阶段。 旨在帮助阐明大脑和认知关键方面的一些机制 健康成年人的衰老，并区分哪些与年龄相关的大脑变化可能发出信号 临床前 AD 与非病理性衰老的第一个目标是检查脑铁。 累积作为认知和神经衰退的早期标志我们将研究其影响。 增加脑铁对认知能力的影响，功能磁共振成像测量健康人的大脑激活 其次，我们的目的是检查突触复杂性的影响。 我们将研究不同风险群体的认知表现和大脑激活。 铁积累和突触复杂性测量与β-淀粉样蛋白的关系 临床前老化和 MCI 的积累，以衡量这些变量是否可以作为 最后，我们计划检验以下假设：病理性衰老的敏感生物标志物。 通过功能磁共振成像测量的神经调节对认知困难的差异可以作为 临床前 AD 的生物标志物预计将提前完成。 了解健康大脑衰老与病理性大脑衰老的机制和预测因素 衰老轨迹。