Neurobiological Substrates of SuperAging and the Preservation of Cingulate Cortex

描述（由申请人提供）：美国总人口中80岁以上的比例呈指数级上升，从而增加了患痴呆症（如阿尔茨海默病）风险最高的人群的频率。拟议的研究通过研究似乎避免退行性疾病过程的人群来解决这一重大的公共卫生挑战。我们的中心确定了一组独特的“超级老人”，80岁以上的人表现出上级记忆功能，并在日常生活中茁壮成长。西北大学的超级老龄化研究的目标是确定解剖学，组织病理学，神经心理学，心理社会学和遗传因素，这些因素解释了这些长寿者的认知能力。一种可能的机制可能与抵抗“正常”衰老和认知能力下降所发生的病理性大脑变化有关。有趣的是，在我们的中心，与对照组相比，SuperAgers的MRI扫描的皮质厚度测量的初步分析发现前扣带皮质（ACC）的厚度更大。此外，对SuperAging大脑的初步死后定性检查揭示了显着的发现：（1）在ACC中几乎没有斑块和缠结-阿尔茨海默病的标志;（2）von Economo神经元（VENS）的密度增加，这是高级灵长类ACC的一个独特特征，涉及复杂推理和高阶认知。这项计划的目的是研究超级老年人扣带皮层的结构和病理特征，因为该区域被证明介导促进记忆的执行功能。目标1将采用神经影像学方法，对大组超级老年人和对照组的扣带回进行详细的感兴趣区域分析，以识别可能代表超级老年人特有解剖学基质的扣带回区域。鉴于先前的研究结果，我们假设与对照组相比，SuperAgers将在ACC与其他扣带区域中增加厚度。目标2将采用组织病理学方法对SuperAgers和对照样本中与衰老相关的死后扣带回特征进行定量，包括斑块和缠结标记物以及VEN计数。基于初步发现，与对照组相比，SuperAgers中扣带回病理特征的频率预计较低，然而，预计SuperAgers中VEN密度最高。将分析目标1中的解剖测量与认知测试表现之间的关系，以确定脑-行为关系，还将分析目标2中的组织病理学特征与认知表现之间的关系。这项多学科研究的结果将为老年人上级认知功能的神经机制提供有价值的信息。该项目是SuperAging研究的一个组成部分，该研究具有高度的转化性，因为研究结果将有助于揭示衰老的神经生物学成分，最终可以指导痴呆症的治疗。神经影像学、组织病理学和认知评估方面的高级培训对于实现这些目标至关重要。

DESCRIPTION (provided by applicant): The proportion of the total US population over age 80 is rising exponentially, thus increasing the frequency of those who are at highest risk for developing dementias such as Alzheimer's disease. The proposed research addresses this major public health challenge by studying a population of individuals who seem to avoid degenerative disease processes. Our center identified a unique group of "SuperAgers", individuals over age 80 who demonstrate superior memory functioning and thrive in daily life. The goal of the SuperAging Study at Northwestern University is to identify the anatomic, histopathologic, neuropsychological, psychosocial, and genetic factors that explain preserved cognition in these long-lived persons. One possible mechanism may be linked with resistance to pathologic brain changes that occur with "normal" aging and cognitive decline. Interestingly, at our Center, preliminary analysis of cortical thickness measures from MRI scans of SuperAgers compared to control groups found greater thickness of the anterior cingulate cortex (ACC). Additionally, preliminary post-mortem qualitative examination of SuperAging brains revealed remarkable findings: (1) virtual absence of plaques and tangles-hallmarks of Alzheimer's disease- in the ACC and (2) increased density of von Economo neurons (VENS), a unique feature of the higher primate ACC implicated in complex reasoning and higher-order cognition. The goal of this proposal is to investigate structural and pathologic features of the cingulate cortex in SuperAgers, as this region is shown to mediate executive functions that facilitate memory. Aim 1 will employ a neuroimaging approach to conduct a detailed region-of-interest analysis of the cingulate in large groups of SuperAgers and controls to identify cingulate areas that may represent anatomic substrates unique to SuperAging. Given prior findings, we hypothesize that SuperAgers will have increased thickness in ACC vs. other cingulate regions compared to controls. Aim 2 will employ a histopathologic approach to quantitate features of post-mortem cingulate as they pertain to aging, including markers of plaques and tangles and counts of VENs, in specimens from SuperAgers and controls. Based on preliminary findings, the frequency of pathologic features in the cingulate is expected to be lower in SuperAgers compared to controls~ VEN density, however, is expected to be greatest in SuperAgers. Relationships between anatomic measures in Aim 1 and performance on cognitive tests will be analyzed to identify brain-behavior relationships~ relationships between histopathologic features in Aim 2 and cognitive performance will also be analyzed. Findings from this multidisciplinary study will provide valuable information on neural mechanisms underlying preservation of superior cognitive functioning in old age. The SuperAging Study, of which this project is an integral part, is highly translational as findings will help reveal the neurobiologic constituents f aging that can ultimately guide treatments for dementias. Advanced training in neuroimaging, histopathology, and cognitive assessment are critical for attainment of these goals.