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

健康衰老和病理之间的区别是不精确的，并被重叠所笼罩。 在与阿尔茨海默病相关的正常脑老化标志物和神经变化中 (Ad)。即使在阿尔茨海默病的关键标志--β-淀粉样蛋白沉积的情况下，20%-30%的健康 老年人表现出淀粉样蛋白升高，但目前尚不清楚这些人是否会 必然会发展成痴呆症。因此，有很大的需要设计研究来 研究新的，较少研究的大脑老化机制，这可能有助于消除 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研究为神经认知老化提供新的视角。 从分子水平探讨脑老化的重要和未被研究的机制 (铁积累和β沉积)到突触变化(轴突复杂性)到 脑功能(BOLD激活调制)及其对中年人认知的影响 年龄较大的和MCI个人。重要的是，我们建议前瞻性地研究健康的老年个体。 谁系统性地存在阿尔茨海默病风险的差异(认知健康低AD风险，认知健康 AD风险增加)，以及轻度认知障碍(MCI)患者，他们 可能处于神经病理发育的早期阶段。通过这种方法，我们 旨在帮助阐明大脑和认知关键方面的一些潜在机制 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 临床前阿尔茨海默病与非病理性衰老。第一个目标是研究大脑中的铁 积聚是认知和神经衰退的早期标志。我们会研究这些措施的影响 健康人脑内铁含量增加对认知功能的影响及功能磁共振成像测量脑激活 年龄、临床前AD和MCI。其次，我们的目标是研究突触复杂性的影响 不同风险群体的认知表现和大脑激活。我们将研究 铁蓄积和突触复杂性指标与β-淀粉样蛋白的关系 临床前衰老和MCI的累积，以衡量这些变量是否可以作为 病理性衰老的敏感生物标志物。最后，我们计划测试假设 通过功能磁共振成像测量的认知困难的神经调节的差异可以作为 临床前AD的生物标志物。目前的研究预计将提前完成 对健康脑老化与病理性脑老化的机制和预测因素的理解 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.