Brain pathologies, reserve and cognition in aging and dementia

 描述(申请人提供)：在生命的最后几十年里，多种脑部疾病以加速的速度积累，认知功能下降。要改变认知老化这一基本事实，还需要多项重大的科学突破。然而，认知下降的速度是高度不同的，大脑病理，即使综合评估，也会让大多数变异无法解释。很明显，在大脑病理的任何水平上，认知障碍的水平都有很大的个体差异。因此，重要的是要了解当病理发生时减少其影响的因素。“储备”是研究保护因素的有用结构，也是本项目的重点。以前的努力创造并验证了一种衡量储备的新方法，称为“储备指数”。储备指数已被证明可以修正从MCI转变为痴呆症的风险，修正认知衰退的速率，并修正进行性脑萎缩对纵向认知衰退的影响。本项目探讨了关于储量的两个关键问题，即储量是如何随时间变化的，以及什么因素构成了储量？因为储备取决于大脑的完整性，积累的病理最终必然会减少储备。因此，在储备改变临床变化率的程度上，测量储备的变化将改善对临床轨迹的预测。以前不可能衡量储备的变化，但这可以通过储备指数来实现。该项目收集纵向体积磁共振成像作为大脑病理的一种测量方法，使用敏感和可靠的神经心理学测试来纵向测量认知功能，并收集可能与储备相关的人口统计、经验和行为因素的数据。目标1是将储备的横断面测量扩展到纵向框架，开发合适的模型，并检验有关储备变化和纵向储备对临床进展的影响的基本假设。目标2调查了可能与较高储备相关的因素，目标3调查了与储备随时间的稳定性有关的相同因素。候选因素是基于对文献的回顾而选择的，这表明认知刺激和挑战、社会参与和体育锻炼都与老年时更好的认知结果有关。还有一种观点认为，关键不在于人们做什么，而在于他们如何做到这一点；“投资特质”--寻求并从事费力的认知活动的倾向--可能会通过增加认知挑战而在很大程度上塑造体验，从而提高储备力。每一种行为因素，包括人格特征， 可以通过干预来修改。提高对储备的理解有可能改善对衰老和疾病中认知能力下降的预测，并指导减少病理影响的新干预措施-从而延迟或可能避免轻度认知障碍(MCI)和痴呆症等临床结果。

 DESCRIPTION (provided by applicant): In the last decades of life multiple brain pathologies accumulate at an accelerating pace and cognitive function declines. Multiple major scientific breakthroughs will be needed to alter this basic fact of cognitive aging. However, rates of cognitive decline are highly heterogeneous and brain pathology, even when comprehensively assessed, leaves most variation unexplained. It is clear that the there are great individual differences in the level of cognitive impairment that is seen at any level of brain pathology. It i therefore important to also understand the factors that reduce the impact of pathology when it occurs. "Reserve" is a useful construct for studying protective factors and is the focus of this project. Prior efforts created and validated a novel approach to the measurement of reserve, termed the "Reserve Index". The Reserve Index has been shown to modify the risk of converting from MCI to dementia, modify rates of cognitive decline, and modify the effects of progressive brain atrophy on longitudinal cognitive decline. This project pursues two key questions about reserve, namely how does it change over time and what factors build reserve? Because reserve depends on the integrity of the brain, accumulating pathology must eventually diminish reserve. Thus, to the extent that reserve modifies rates of clinical change, measuring changes in reserve will improve prediction of clinical trajectories. It has not previously been possible to measure changes in reserve, but this can be done with the Reserve Index. This project collects longitudinal volumetric MRI as a measure of brain pathology, uses sensitive and reliable neuropsychological tests to measure cognitive function longitudinally, and gathers data on demographic, experiential, and behavioral factors potentially related to reserve. Aim 1 is to extend the cross sectional measurement of reserve to a longitudinal framework, to develop appropriate models, and to test basic hypotheses about change in reserve and the effect of longitudinal reserve on clinical progression. Aim 2 investigates factors that may be associated with higher reserve, and Aim 3 investigates the same factors in relation to stability of reserve over time. Candidate factors were selected based on review of the literature, which suggests that cognitive stimulation and challenge, social engagement and physical exercise are all associated with better cognitive outcomes in old age. It has also been argued that it is not what people do but rather how they do it; "investment traits"-the tendency to seek and engage in effortful cognitive activities- may broadly shape experience by increasing cognitive challenge and thus contribute to reserve. Each of these behavioral factors, including the personality traits, can be modified by interventions. Improved understanding of reserve has the potential to improve the prediction of cognitive decline in aging and disease and to guide new interventions that reduce the impact of pathology-thus delaying, or possibly avoiding clinical outcomes like mild cognitive impairment (MCI) and dementia.