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

健康老龄化和病理学之间的区别是不精确的，并且由于重叠而模糊不清 在正常的大脑老化标记物和与阿尔茨海默病相关的神经变化中， （AD）。即使在β-淀粉样蛋白沉积的情况下，AD的一个关键标志，20-30%的健康人 老年人显示淀粉样蛋白升高，但尚不清楚这些人是否会 必然发展为痴呆症。因此，非常需要进行研究， 研究新的，较少研究的大脑衰老机制，这可能有助于消除 神经变化是病理轨迹的早期指标，而不是正常衰老的迹象。 本研究的目的是提供新的见解，神经认知老化与多模态 从分子变化研究脑衰老的重要和未充分研究的机制 (iron聚集和Aβ沉积）到突触变化（神经突复杂性）到 大脑功能（BOLD激活调制）及其对中年人认知的影响， 老年人和MCI患者。重要的是，我们建议前瞻性地研究健康的老年人 系统性地改变AD风险（认知健康AD低风险，认知健康 AD的风险升高）以及轻度认知障碍（MCI）患者， 可能处于神经病理学发展的早期阶段。通过这种方法，我们 旨在帮助阐明大脑和认知的一些关键方面的机制， 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预示着 临床前AD与非病理性衰老。第一个目标是检查大脑铁 累积作为认知和神经衰退的早期标志。我们将研究 增加脑铁对认知能力的影响，以及fMRI测量健康人的脑激活 衰老、临床前AD和MCI。其次，我们的目标是研究突触复杂性的影响， 对认知能力和大脑活动的影响。我们会研究 铁积累和突触复杂性测量与β-淀粉样蛋白的关系 累积在临床前老化和MCI，以衡量这些变量是否可以作为 病理老化的敏感生物标志物。最后，我们计划测试假设， 用功能磁共振成像测量的认知困难的神经调制的差异可以作为一个 临床前AD的生物标志物。目前的研究预计将提前完成 了解健康大脑老化与病理性大脑老化的机制和预测因素， 老化轨迹

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.