Brain pathologies, reserve and cognition in aging and dementia

描述(申请人提供)：这项研究试图更好地了解衰老和痴呆症患者大脑病理与认知功能的关系。个体的心智能力随着年龄的变化有惊人的变化；有些人的变化很小，如果有变化的话，其他人会有严重的、令人衰弱的下降。为什么，这是未知的。一种解释是大脑病理，如阿尔茨海默病(AD)和脑梗塞(中风)。AD是痴呆症的主要原因，发展缓慢，实际上可能在出现明显症状之前几十年就开始在大脑中出现。大多数高龄老人都存在一定程度的AD改变和血管疾病。然而，将病理学与认知功能联系起来的研究通常无法解释大部分差异。一个潜在的原因可能是这种病理没有得到充分的衡量。或者，可能是大脑病理，无论测量多么精致，都无法充分解释认知损失，因为这些因素缓和了病理的影响。这一解释是在“储备”的概念中发展起来的，该概念认为一些与生俱来和后天获得的特征形成了一种缓冲，提供了一定程度的保护，免受大脑病理的影响。这是一个对公共健康具有巨大潜在重要性的概念，因为它表明，只要这些因素是可以改变的，人们就可以采取措施，实质上保护自己免受一系列常见和令人衰弱的大脑疾病的影响。我们建议比以前更好地测量大脑病理，建立病理对认知功能的影响的模型，然后使用这些改进的模型来更好地理解Reserve作为大脑病理影响的调节因子的作用。之前研究的一个主要障碍是无法测量一生中阿尔茨海默病的存在。最近对β淀粉样蛋白(一种在阿尔茨海默病中至关重要的异常蛋白质片段)示踪剂的开发改变了这一点。我们将使用PET和示踪剂匹兹堡B(PIB)来量化大脑淀粉样蛋白的范围，并将获得脑结构病理(萎缩、梗死和白质病变)的MRI测量，从而模拟这两种主要年龄相关病理对认知功能的联合影响。然后，我们将使用这一努力的结果来研究储备。我们将在一个种族多元化的样本中这样做，这个样本具有广泛的教育程度，这通常被认为是储备的标志，并将使用具有优越测量特性的神经心理测试。因此，我们将能够比以往任何时候都更好地表征生命中的大脑病理水平，并将这些发现与认知功能联系起来，特别是在广泛的假设储备范围内进行测量。

DESCRIPTION (provided by applicant): This study seeks to better understand the relationship of brain pathology to cognitive function in aging and dementia. There is striking variability in how individuals' mental abilities change with age; some people change little, if any, others have major, debilitating drops. Why, is unknown. One explanation is brain pathologies such as Alzheimer's disease (AD) and infarcts (strokes). AD, which is the predominant cause of dementia, develops slowly and may actually begin to appear in brain decades before overt symptoms are appear. Some degree of AD changes and vascular disease is present in most very old people. However, studies that relate pathology to cognitive function generally fail to explain most of the variance. One potential reason may be that the pathology has been inadequately measured. Alternatively, it may be that brain pathology, no matter how exquisitely measured, will never explain cognitive losses adequately because of factors that moderate the impact of pathology. This explanation has been developed in the concept of "reserve", the idea that some set of innate and acquired characteristics form a buffer that provides a degree of protection against the impact of brain pathology. It is a concept that holds enormous potential importance for public health because it suggests that, to the degree these factors are modifiable, people can take steps to substantially protect themselves against a broad array of common and debilitating brain conditions. We propose to measure cerebral pathology better than has been done previously, to model the effects of pathology on cognitive function, and then to use these improved models to better understand the role of reserve as a moderator of the impact of brain pathology. A major barrier to previous investigation has been the inability to measure the presence of Alzheimer's disease during life. The recent development of tracers for beta amyloid (an abnormal protein fragment critical in AD) changes this. We will use PET with the tracer Pittsburgh B (PIB) to quantify the extent of cerebral amyloid, and will obtain MRI measures of structural brain pathology (atrophy, infarcts and white matter lesions) and thus model the joint effects of the two major age- associated pathologies on cognitive function. We will then use the results of that effort to study reserve. We will do so in an ethnically diverse sample that has a wide range of education, which is generally thought to be a marker for reserve, and will use neuropsychological tests with superior measurement properties. Thus we will be able to characterize brain pathology levels during life better than has ever been done before and relate those findings to cognitive function that is measured especially well across a broad spectrum of putative reserve.