Neural and Biochemical Mechanisms of Cognitive Aging

项目总结 认知老化领域长期以来一直在争论症状前脑部疾病是否能解释 被认为是与年龄相关的正常认知下降的比例。这一点最值得注意的是 阿尔茨海默病(AD)不仅是因为它是一种高度流行的与年龄相关的疾病，而且还因为 阿尔茨海默病的几个特征在正常衰老中表现出来。尤其是情节记忆的下降，？-的沉积。 淀粉样斑块和神经纤维缠结相关的海马区萎缩是AD的所有方面，也是 常见于认知功能正常的老年人。然而，阿尔茨海默病的病理效应并不简单 可能由可被描述为脆弱性和储备性的介入性因素所调节。在 在过去的几年里，科学的进步使得可以测量可能 参与这种与年龄相关的记忆力丧失模型。因此，用正电子测量淀粉样蛋白是可能的。 发射断层扫描(PET)和淀粉样蛋白显像剂[11C]匹兹堡化合物B(PIB)，以评估 应用磁共振成像(MRI)检测神经原纤维缠绕负荷和海马区萎缩程度，并评价 使用PET测量葡萄糖代谢的储备过程(使用[18F]-氟代脱氧葡萄糖，或FDG)和 使用功能磁共振成像(FMRI)。 在这个项目中，将在5年内仔细招募125名认知完好的老年人。 以整体认知和情景记忆为特征，并用PIB-和FDG-PET成像进行研究 和结构核磁共振。将对其中50名受试者和50名健康的年轻受试者进行研究。 通过fMRI和与事件相关的行为范式对比成功 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区萎缩不同于具有这些特征的老年人，而且 年轻人。此外，关键假设将在连续的多变量模型中进行检验，在这些模型中，PET 海马萎缩的淀粉样蛋白测量和磁共振测量预计与较差的 间歇性记忆功能，而休息的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，大脑内侧的活动减少，预计会有发现。 颞叶可能与淀粉样蛋白沉积有关，而更好的表现可能与增加 前额叶皮质激活。最后，一组受试者将每两年重新评估一次，以了解 这些测量是否预测了认知随时间的变化。总而言之，这个项目将提供一个 描述了独立于大脑淀粉样蛋白沉积的最佳认知老化，并将开始解开 衰老过程中记忆功能丧失和保存的相关机制。

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.