Neural Processes Underlying Cognitive Aging

描述（由申请人提供）：本提案旨在描述影响正常衰老中认知的神经过程，而不是早期病理变化。临床正常衰老中存在多种脑变化，包括白质破坏、神经递质系统耗竭和临床前阿尔茨海默病（AD）病理。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，但分离提高了某些成分可能反映正常衰老而独立于临床痴呆进展的可能性。例如，我们最近观察到，在没有淀粉样蛋白沉积的情况下，正常衰老中的白质完整性与执行功能障碍有关。高龄还与皮质系统的招募增加（通常是双侧）有关，类似于在大脑系统受到压力的其他情况下观察到的情况。活动增加在老年人中表现突出，作为一个群体，他们表现出上述大脑变化，这提高了他们反映代偿反应的可能性。测试与认知衰老相关的假设是具有挑战性的，因为很难确定一个没有AD临床前病理阶段的正常老年人的纯队列。作为一种研究认知衰老的新方法，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衰老与执行功能障碍之间的联系。具体来说，我们的目标是(1)探索大规模脑网络的破坏（通过DTI和fcMRI）是否在没有淀粉样蛋白沉积的情况下解释认知变化；(2)探索正常衰老中是否存在独立于临床前AD的与mtl相关的记忆差异；(3)探索正常衰老中是否存在活动增加并减轻认知下降。我们假设在正常衰老过程中存在一个影响执行功能的显著级联反应，该反应独立于淀粉样斑块病理，而活动增加是减轻该级联反应影响的一种反应。级联被认为是由白质破坏和大规模脑系统协调受损引起的。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规范数据集，其中包括结构、功能和认知数据，这些数据按淀粉样蛋白沉积的高低分层。

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.