Oregon Brain Aging Study

描述（由申请人提供）： 俄勒冈州脑老化研究（OBAS）是一项纵向研究，研究与年龄最大的老年人（85岁）健康脑老化相关的因素，这些老年人是人口增长最快的部分，也是痴呆症风险最高的人群。在过去的20年中，OBAS已经检查了一系列标志物（如脑容量，临床特征，遗传学和脑病理学）的衰老变化的轨迹和意义，确定了一个十年或更长时间的潜伏期，当个体在发展为坦率的痴呆症之前似乎患有症状前疾病。在导致这一潜伏期认知能力下降的因素中，与血管疾病有关的因素最为突出。这种与衰老相关的血管疾病的一个突出标志物通常见于大脑的磁共振成像（MRI），表现为白色高信号（WMH）。这些WMH对大脑功能具有重要意义，因为白色物质包含协调大脑功能的关键途径。这些通路的中断与显著的认知和运动障碍有关。了解导致WMH和相关白色物质破坏的机制对于最终治疗或预防与脑血管疾病相关的认知和功能下降至关重要。因此，在本申请中，我们建议通过使用新的高场MRI技术评估脑血流量（CBF）和脑中相关的微结构白色物质破坏来检查导致这种高度普遍的白色物质变化的最古老的潜在机制。为了实现这一目标，我们将追求三个密切相关的研究目标。首先，我们建议确定无创动脉自旋标记（ASL）MRI测量的CBF变化在WMH发展中的作用，以确定是否改变CBF存在于正常出现的白色物质中的老年人与WMH已经存在于他们的大脑中，如果随着时间的推移，改变CBF先于病理性白色物质变化的形成。其次，我们计划通过检查弥散张量成像（DTI）MRI观察到的微结构白色物质破坏程度，来表征与脑血管疾病标志物（如低CBF和高WMH体积）相关的白色物质破坏程度。最后，我们计划确定MRI标志物（CBF，WMH体积，大脑完整性），最好地预测临床（认知和运动）下降的速度和死后大脑病理学，这些病理学与生命中的这些变化最密切相关。该项目将由100多名OBAS年龄最大的老年志愿者进行，他们将每年进行标准化的临床和MRI评估。MRI将需要使用3特斯拉和特殊的7特斯拉MRI仪器，以提供随时间推移的CBF（ASL）和微结构（DTI）损伤的高分辨率图像。考虑到队列的性质，相当多的人已经并将捐献他们的大脑用于研究，允许死后识别MRI和在生命期间观察到的其他临床变化，这些变化最好地指示尸检时发现的神经病理学。作为这项工作的一部分，100多名在过去20年中每年进行MRI扫描并死亡的OBAS参与者提供的独特数据将用于检查他们一生中的WMH体积积累，以及这种变化如何与主要年龄相关的病理学（血管以及阿尔茨海默病病变）在他们的大脑尸检中看到。

DESCRIPTION (provided by applicant): The Oregon Brain Aging Study (OBAS) is a longitudinal study of factors related to healthy brain aging in the oldest old (those e age 85), the fastest growing segment of the population and those at highest risk for dementia. During the past 20 years the OBAS has examined the trajectory and meaning of aging change across a range of markers such as brain volumes, clinical profiles, genetics and brain pathology, identifying a latent period of a decade or more when individuals appear to have presymptomatic disease prior to developing frank dementia. Among factors leading to cognitive decline in this latent period, those related to vascular disease stand out. A prominent marker of this vascular disease associated with aging is commonly seen on magnetic resonance imaging (MRI) of the brain and appears as white matter hyperintensities (WMHs). These WMHs have important implications for brain function since the white matter contains critical pathways for coordinated brain function. Disruption of these pathways is associated with significant cognitive and motor impairments. Understanding the mechanisms that lead to WMHs and related disruption of the white matter is fundamental to ultimately treating or preventing cognitive and functional decline associated with cerebrovascular disease. Accordingly, in this application we propose to examine in the oldest old, underlying mechanisms leading to this highly prevalent white matter change by assessing cerebral blood flow (CBF) and related microstructural white matter disruption in the brain using new high field MRI techniques. To achieve this goal we will pursue three tightly related research aims. First, we propose to determine the role of changes in CBF measured with non-invasive arterial spin labeling (ASL) MRI on the development of WMHs to determine if altered CBF is present in normal appearing white matter in elderly with WMHs already present in their brain, and if over time, altered CBF precedes the formation of pathologic white matter change. Second, we plan to characterize the extent of white matter disruption related to cerebrovascular disease markers such as low CBF and high volumes of WMH by examining the extent of microstructural white matter disruption seen with diffusion tensor imaging (DTI) MRI. Finally, we plan to Identify MRI markers (CBF, WMH volume, brain integrity) that best predict rates of clinical (cognitive and motor) decline and the post mortem brain pathologies that are most closely tied to these changes during life. The project will be conducted with over 100 OBAS oldest old volunteers who will have annual standardized clinical and MRI assessments. MRI will entail the use of both 3 Tesla and a special 7 Tesla MRI instrument to provide high-resolution images of CBF (ASL) and microstructural (DTI) damage over time. Given the nature of the cohort a significant number have and will donate their brain for study allowing for post mortem identification of MRI and other clinical changes observed during life that best index the neuropathologies found on autopsy. As part of this effort, unique data contributed by over 100 OBAS participants who had annual MRI scans and died during the prior 20 years will be used to examine WMH volume accumulation during their lives and how this change relates to the major age-associated pathologies (vascular as well as Alzheimer's disease lesions) seen at post mortem examination of their brain.