Neural and Biochemical Mechanisms of Cognitive Aging

描述(申请人提供)：认知老化领域长期以来一直在争论症状前大脑疾病是否占被认为是正常的与年龄相关的认知下降的比例。这在阿尔茨海默病(AD)方面最为显著，不仅因为它是一种高度流行的与年龄相关的疾病，而且还因为AD的几个特征在正常衰老中可见。特别是，情景记忆的下降、淀粉样斑块的沉积以及与神经纤维缠结相关的海马区萎缩都是阿尔茨海默病的一些方面，在认知功能正常的老年人中也很常见。然而，AD病理的影响并不是直截了当的，很可能是由可以被描述为脆弱性和储备性的介入性因素调节的。在过去的几年里，科学的进步使得对这种与年龄相关的记忆丧失模型可能涉及的多种过程进行了测量。因此，有可能用正电子发射断层扫描(PET)和淀粉样蛋白显像剂[11C]匹兹堡化合物B(PIB)来测量淀粉样蛋白，用磁共振成像(MRI)来评估神经纤维缠绕负荷和海马区萎缩，并通过葡萄糖代谢的PET测量(使用[18F]-氟脱氧葡萄糖，或FDG)和功能磁共振(FMRI)来评估储备过程。 在这个项目中，将在5年内招募一组认知正常的125名老年人，他们在总体认知和情景记忆方面进行了仔细的表征，并进行了PIB-和FDG-PET成像和结构磁共振研究。这些受试者中的一个小组，以及50名健康的年轻受试者，将接受功能磁共振成像和一种事件相关行为范式的研究，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体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以及年轻人不同。此外，关键假说将在连续的多变量模型中进行检验，在该模型中，PET测量的淀粉样蛋白和MR测量的海马区萎缩预计与较差的情景记忆功能有关，而休息的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的认知活动中，预计也会有类似的发现，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增加前额叶皮质激活有关。最后，一组受试者将每隔两年重新评估一次，看看这些测量是否可以预测认知随时间的变化。总而言之，该项目将提供独立于大脑淀粉样蛋白沉积的最佳认知老化的描述，并将开始揭开与衰老中记忆功能丧失和保存相关的机制。 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的正常老年人经历的记忆丧失。这对于理解AD和正常衰老之间的关系，以及开发在衰老过程中优化大脑功能的方法都是重要的。

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.