Neural Processes Underlying Cognitive Aging

描述(由申请人提供)：本提案试图描述在正常衰老中影响认知的神经过程的特征，区别于病理变化的早期阶段。在临床正常衰老过程中会出现多种脑部改变，包括白质破坏、神经递质系统衰竭和临床前阿尔茨海默病(AD)的病理改变。虽然所有这些大脑变化都出现在同一个人身上是很常见的，但分离增加了这样一种可能性，即某些成分可能反映了正常衰老，而与临床痴呆症的进展无关。例如，我们最近观察到，正常衰老中的白质完整性与缺乏淀粉样蛋白沉积的执行功能障碍有关。高级衰老还与皮质系统招募的增加(通常是双侧)有关，类似于在其他大脑系统受到压力的情况下观察到的情况。活动增加在老年人中尤为明显，他们作为一个群体，表现出上面提到的大脑变化，这增加了它们反映代偿反应的可能性。测试与认知老化相关的假说是具有挑战性的，因为要确定一个纯粹的正常老年人队列是极其困难的，这些人在AD病理的临床前阶段被排除在外。作为研究认知老化的一种新方法，我们将在一组使用PET分子标记筛选淀粉样蛋白沉积存在的老年人中探索大脑老化和执行功能障碍之间的联系。具体地说，我们的目标是(1)探索在没有淀粉样蛋白沉积的情况下，大规模脑网络(通过DTI和fcMRI)的破坏是否解释了认知差异，(2)探索正常衰老是否存在独立于临床前AD的MTL相关记忆差异，以及(3)探索正常衰老是否存在活动增加和缓解认知衰退。我们假设，在正常衰老过程中，存在独立于淀粉样斑块病理的影响执行功能的显着级联反应，活动增加是减轻这种级联反应的反应。这种级联反应被认为是由于脑白质的破坏和大规模大脑系统的协调受损造成的。通过完成这个项目，除了测试我们的特定假设外，我们还将生成并公开共享一个关于衰老的标准化数据集，其中包括按淀粉样蛋白沉积高低分层的结构、功能和认知数据。 与公共卫生相关：越来越多的人口远远超过退休年龄。在这里，我们试图了解正常衰老中损害认知的大脑因素，以及补偿以缓解认知衰退。通过了解这些因素，我们希望促进健康、优雅的衰老。

DESCRIPTION (provided by applicant): The present proposal seeks to characterize neural processes that affect cognition in normal aging distinct from early-stages of pathological change. Multiple brain changes are present in clinically normal aging including white-matter disruption, depletion of neurotransmitter systems, and preclinical Alzheimer's disease (AD) pathology. While it is common for all of these brain changes to be present in the same individuals, dissociations raise the possibility that certain components may reflect normal aging independent of the progression to clinical dementia. For example, we recently observed that white-matter integrity in normal aging was linked to executive dysfunction in the absence of amyloid deposition. Advanced aging is also associated with increased (often bilateral) recruitment of cortical systems, similar to that observed in other situations where brain systems are stressed. Activity increases are prominent in older adults who, as a group, display the brain changes noted above raising the possibility that they reflect a compensatory response. Testing hypotheses associated with cognitive aging is challenging because it is extremely difficult to identify a pure cohort of normal older adults that is sparred the preclinical stages of AD pathology. As a novel approach to the study of cognitive aging, we will explore the link between brain aging and executive dysfunction in a group of older adults screened for the presence of amyloid deposition using PET molecular markers. Specifically, we aim to (1) explore whether disruption of large-scale brain networks (via DTI and fcMRI) accounts for cognitive variation in the absence of amyloid deposition, (2) explore whether there is MTL-linked memory variance in normal aging that is independent of preclinical AD, and (3) explore whether activity increases are present in normal aging and mitigate cognitive decline. We hypothesize that there exists a prominent cascade affecting executive function during normal aging that is independent of amyloid plaque pathology and that activity increases are a response to mitigate the effects of this cascade. The cascade is proposed to arise from white-matter disruption and impaired coordination of large-scale brain systems. By completing this project, in addition to testing our specific hypotheses, we will generate and openly share a normative data set on aging that includes structural, functional, and cognitive data that is stratified by high or low amyloid deposition. PUBLIC HEALTH RELEVANCE: An increasing percentage of the population is living well beyond retirement age. Here we seek to understand the brain factors in normal aging that impair cognition as well as compensate to mitigate cognitive decline. By understanding these factors we hope to promote healthy, graceful aging.