Neural and Biochemical Mechanisms of Cognitive Aging

项目摘要 认知老化领域长期以来一直在争论症状前脑部疾病是否是导致老年痴呆症的原因。 被认为是正常的年龄相关的认知能力下降的比例。这是最值得注意的关系到 阿尔茨海默病（AD）不仅是因为它是一种高度流行的年龄相关疾病，而且还因为 AD的几个特征在正常衰老中可见。尤其是情景记忆的衰退， 淀粉样斑块和神经元缠结相关的海马萎缩是AD的所有方面， 常见于认知功能完好的老年人然而，AD病理学的影响并不直接， 很可能受到可以被描述为脆弱性和保留的干预因素的影响。内 在过去的几年里，科学的进步已经允许测量多种过程， 与年龄相关的记忆丧失有关。因此，可以用正电子探针测量淀粉样蛋白。 发射断层扫描（PET）和淀粉样蛋白显像剂[11 C]匹兹堡化合物B（PI B），以评估 通过磁共振成像（MRI）检测神经元缠结负荷和海马萎缩，并评估 储备过程与PET葡萄糖代谢措施（使用[18 F]-氟脱氧葡萄糖，或FDG）和 功能性磁共振成像（fMRI） 在这个项目中，一组125名老年认知完整的个人将被招募超过5年，仔细 以整体认知和情景记忆为特征，并采用PIB和FDG-PET成像进行研究 和结构核磁共振成像将对其中50名受试者沿着50名健康年轻受试者进行研究 与功能磁共振成像和事件相关的行为范式，对比大脑活动， 记住和忘记的物品一个主要的问题是，没有证据的老年人是否以及如何- 淀粉样蛋白沉积或海马萎缩与具有这些特征的老年人不同， 年轻人此外，将在连续多变量模型中检验关键假设，其中PET 淀粉样蛋白的测量和海马萎缩的MR测量预计与较差的相关 情景记忆功能，而静息前额叶葡萄糖代谢将减弱这种关系。类似 在使用功能磁共振成像的认知活动中，预期会出现这样的结果，即内侧大脑活动减少， 颞叶可能与淀粉样蛋白沉积有关，更好的表现可能与增加 前额叶皮层激活最后，将每隔2年对一个受试者亚组进行重新评价，以了解 这些指标是否能预测认知随时间的变化。总的来说，这个项目将提供一个 最佳认知老化的描述独立于大脑淀粉样蛋白沉积，并将开始解开 与衰老过程中记忆功能丧失和保存相关的机制。

PROJECT SUMMARY The cognitive aging field has long debated whether presymptomatic brain disease accounts for a proportion of what is considered to be normal age-related cognitive decline. This is most notable in relation to Alzheimer's disease (AD) not only because it is a highly prevalent age-associated condition, but also because several features of AD are seen in normal aging. In particular, decline in episodic memory, deposition of ¿- amyloid plaques, and neurofibrillary tangle-related hippocampal atrophy are all aspects of AD that are also common in cognitively intact older people. However, the effects of AD pathology are not straightforward and are likely to be mediated by intervening factors that can be characterized as vulnerability and reserve. Within the past several years, scientific advances have allowed the measurement of the multiple processes that may be involved in this model of age-related memory loss. Thus, it is possible to measure ¿-amyloid with positron emission tomography (PET) and the amyloid imaging agent [11C] Pittsburgh Compound B (PIB), to assess neurofibrillary tangle burden and hippocampal atrophy with magnetic resonance imaging (MRI), and to assess reserve processes with PET measures of glucose metabolism (using [18F]-Flurodeoxyglucose, or FDG) and with functional MRI (fMRI). In this project, a group of 125 older cognitively intact individuals will be recruited over 5 years, carefully characterized in terms of overall cognition and episodic memory, and studied with PIB- and FDG-PET imaging and structural MRI. A subgroup of 50 of these subjects, along with 50 healthy young subjects will be studied with fMRI and an event-related behavioral paradigm that contrasts brain activity during successfully remembered and forgotten items. A major question is whether, and how, older people without evidence of ¿- amyloid deposition or hippocampal atrophy differ from older people with these characteristics, and from younger people. In addition key hypotheses will be tested in continuous multivariate models in which PET measures of ¿-amyloid and MR measures of hippocampal atrophy are expected to be related to poorer episodic memory function, while resting prefrontal glucose metabolism will attenuate this relationship. Similar findings are expected during cognitive activity using fMRI, in which diminished brain activity in the medial temporal lobes may be related to ¿-amyloid deposition, and better performance may be related to increased prefrontal cortical activation. Finally, a subgroup of subjects will be re-evaluated at a 2-year interval to see whether these measures predict change over time in cognition. In total, this project will both provide a description of optimal cognitive aging independent of brain amyloid deposition, and will begin to unravel the mechanisms associated with the loss and preservation of memory function in aging.