Neurobiological Substrates of SuperAging and the Preservation of Cingulate Cortex

描述（由申请人提供）：美国80岁以上人口的比例呈指数级增长，从而增加了那些患老年痴呆症（如阿尔茨海默病）的高危人群的频率。拟议的研究通过研究似乎避免退行性疾病过程的个体群体来解决这一重大的公共卫生挑战。我们的中心确定了一个独特的“超级老人”群体，80岁以上的人表现出卓越的记忆功能，并在日常生活中茁壮成长。美国西北大学的超级衰老研究的目标是确定解剖学、组织病理学、神经心理学、社会心理和遗传因素，以解释这些长寿人士保持认知能力的原因。一种可能的机制可能与抵抗“正常”衰老和认知能力下降时发生的病理性大脑变化有关。有趣的是，在我们的研究中心，与对照组相比，通过MRI扫描对超级老年人皮层厚度的初步分析发现，他们的前扣带皮层（ACC）厚度更大。此外，对超级衰老大脑的初步尸检定性检查揭示了显著的发现：(1)前扣带皮层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，这是高级灵长类动物前扣带皮层的一个独特特征，与复杂推理和高阶认知有关。这项提议的目的是研究超级老人扣带皮层的结构和病理特征，因为该区域被证明可以调节促进记忆的执行功能。目的1将采用神经成像方法对大群超级老年人和对照组的扣带进行详细的兴趣区域分析，以确定可能代表超衰老特有的解剖底物的扣带区域。鉴于先前的研究结果，我们假设与对照组相比，超级老人的ACC与其他扣带区域的厚度会增加。目标2将采用组织病理学方法定量分析死后扣带的特征，因为它们与衰老有关，包括斑块和缠结的标记以及VENs的计数，这些都是来自超级老人和对照组的标本。根据初步研究结果，与对照组相比，超级老年人扣带区病理特征的频率预计会较低~然而，超级老年人的VEN密度预计会最大。我们将分析Aim 1的解剖学指标与认知测试表现之间的关系，以确定大脑行为之间的关系；Aim 2的组织病理学特征与认知表现之间的关系也将进行分析。这项多学科研究的发现将为老年高级认知功能保存的神经机制提供有价值的信息。该项目是“超级衰老研究”（SuperAging Study）的一个组成部分，它具有高度的翻译意义，因为研究结果将有助于揭示衰老的神经生物学成分，从而最终指导痴呆症的治疗。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.