Neural and Biochemical Mechanisms of Cognitive Aging

描述（由申请人提供）：认知老化领域长期以来一直在争论症状前脑疾病是否占正常年龄相关认知下降的比例。这在阿尔茨海默病（AD）中是最值得注意的，不仅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。特别是，情景记忆下降，淀粉样蛋白斑块沉积和神经元缠结相关的海马萎缩是AD的所有方面，在认知完整的老年人中也很常见。然而，AD病理学的影响并不直接，可能是由干预因素介导的，这些因素可以被描述为脆弱性和储备。在过去的几年里，科学的进步已经允许测量可能参与这种与年龄有关的记忆丧失模型的多个过程。因此，可以用正电子发射断层扫描（PET）和淀粉样蛋白显像剂[11 C]匹兹堡化合物B（PI B）测量β-淀粉样蛋白，用磁共振成像（MRI）评估神经元缠结负荷和海马萎缩，用葡萄糖代谢的PET测量（使用[18 F]-氟脱氧葡萄糖或FDG）和功能性MRI（fMRI）评估储备过程。 在这个项目中，一组125名老年认知功能完好的人将被招募超过5年，仔细的整体认知和情景记忆方面的特点，并与PIB和FDG-PET成像和结构MRI研究。这些受试者中有50人组成的一个亚组，沿着50名健康的年轻受试者，将用功能磁共振成像和一种事件相关的行为范式进行研究，该范式对比了成功记住和忘记物品时的大脑活动。一个主要的问题是，没有淀粉样蛋白沉积或海马萎缩证据的老年人是否以及如何与具有这些特征的老年人和年轻人不同。此外，将在连续多变量模型中检验关键假设，其中戊淀粉样蛋白的PET测量和海马萎缩的MR测量预计与较差的情景记忆功能相关，而静息前额叶葡萄糖代谢将减弱这种关系。在使用功能磁共振成像进行认知活动时，预期会有类似的发现，其中内侧颞叶的大脑活动减少可能与淀粉样蛋白沉积有关，而更好的表现可能与前额叶皮质激活增加有关。最后，将以2年的间隔重新评估一个受试者亚组，以观察这些指标是否预测认知随时间的变化。总的来说，这个项目将提供一个独立于大脑淀粉样蛋白沉积的最佳认知衰老的描述，并将开始解开与衰老中记忆功能丧失和保留相关的机制。 公共卫生相关性：该项目将评估阿尔茨海默病是否以及如何解释健康正常老年人的记忆丧失。这对于理解AD和正常衰老之间的关系以及开发优化衰老中大脑功能的方法都很重要。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project will assess whether and how Alzheimer's disease may account for the memory loss experienced by healthy normal older people. This is important both for understanding relationships between AD and normal aging, and for developing ways of optimizing brain function in aging.