Brain pathologies, reserve and cognition in aging and dementia

 描述（由申请人提供）：在生命的最后几十年，多种脑部病变以加速的速度积累，认知功能下降。需要多项重大科学突破来改变认知老化的基本事实。然而，认知能力下降的速度是高度异质性的，即使经过全面评估，大脑病理学也无法解释大多数变化。很明显，在大脑病理学的任何水平上，认知障碍的水平都存在很大的个体差异。因此，重要的是要了解减少病理发生时的影响的因素。“储备”是研究保护因素的一个有用的概念，也是本项目的重点。先前的努力创造和验证了一种新的方法来衡量储备，称为“储备指数”。储备指数已被证明可以改变从MCI转化为痴呆的风险，改变认知下降的速度，并改变进行性脑萎缩对纵向认知下降的影响。这个项目追求两个关键问题的储备，即它如何随着时间的推移而变化，什么因素建立储备？因为储备取决于大脑的完整性，累积的病理最终会减少储备。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临床轨迹的预测。以前不可能衡量储备的变化，但可以用储备指数来衡量。该项目收集纵向容积MRI作为脑病理学的测量，使用敏感和可靠的神经心理学测试来纵向测量认知功能，并收集与储备相关的人口统计学，经验和行为因素的数据。目的1是将储备的横截面测量扩展到纵向框架，开发适当的模型，并测试关于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调查可能与较高储备有关的因素，目标3调查与储备长期稳定性有关的相同因素。候选因素的选择是基于对文献的回顾，这表明认知刺激和挑战，社会参与和体育锻炼都与老年人更好的认知结果相关。也有人认为，重要的不是人们做了什么，而是他们如何做;“投资特质”--寻求和参与努力的认知活动的倾向--可能通过增加认知挑战来广泛塑造经验，从而有助于储备。每一个行为因素，包括人格特征， 可以通过干预来改变。对储备的进一步了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.