Cognitive Abilities of At-Risk Elderly for Dementia

描述（由申请人提供）：阿尔茨海默病（AD）最严重地影响我们人口中增长最快的部分：80岁及以上的人。在AD的临床前阶段识别非痴呆患者的能力将对改善早期诊断和使用抗痴呆药物治疗产生深远的影响。如果在最早阶段应用神经保护治疗将是最有效的，这为准确的临床前检测提供了重要的理论基础。然而，剩下的障碍之一集中在识别AD患者的困难之前，他们的赤字成为临床显着。考虑到与正常衰老相关的认知和大脑变化与AD的认知和大脑变化重叠的程度，准确检测晚期年龄组的早期AD提出了许多独特的挑战。我们建议进行一项为期五年的纵向研究非常老（年龄80岁及以上），其中将检查神经心理学，神经影像学和遗传评估的组合，相对于年轻的老年人（年龄60-79），以确定最显着的AD临床前标志物。我们在前一个项目期间的工作揭示了临床和临床前AD中认知和大脑变化表达的年龄和遗传风险的重要差异。然而，还有很多工作要做，在非常古老的进展到AD的特点。通过使用新兴的神经心理学（例如，认知差异测量）和功能性磁共振成像（FMRI）技术（例如，联合动脉自旋标记/血氧水平依赖性[ASL/BOLD]成像）将提高我们理解与风险人群中AD发展相关的独特特征的能力。对AD转换的另一个危险因素轻度认知障碍（MCI）的严格检查也将代表该项目的新目标。因此，该更新期的具体目的是（a）确定与非常老年人中AD的临床前阶段相关的保留和受损的认知过程的概况，（B）确定MCI的新定义方案的临床有效性、其临床结果，以及年轻老年人和非常老年人之间是否存在MCI及其各种亚型的差异率，（c）使用组合ASL/BOLD FMRI来测量内侧颞叶（MTL）和相关结构（例如，海马旁回，后扣带回），用于定量估计情节记忆编码期间的脑耗氧代谢率（CMRO 2），和（d）整合神经心理学和神经成像方法，以更好地确定指示年轻-老年和非常-老年之间的AD临床前期的脑和行为变化的概况和进展。公共卫生相关性：尽管在过去十年中神经心理学和神经影像学方法取得了许多进展，但一直缺乏集中于整合这些发现以预测阿尔茨海默病（AD）进展的努力，特别是对于我们最易感的人群（即，80岁及以上）。拟议的研究解决了这一差距，并建立在我们的经验，详细的神经心理学研究沿着与先进的功能磁共振成像研究的内侧颞叶应用于高危人群。随着功能磁共振成像技术在AD研究中的应用，人们越来越需要能够更准确地反映AD临床前期神经活动及其前期变化的定量指标。该项目的主要目标是确定老年人的神经心理学和神经影像学变化的风险，为发展中国家的AD。我们的具体目标继续关注我们已知的最高风险群体（即，80岁及以上的人）和遗传易感性（例如，载脂蛋白E）。对进展为AD的另一个风险因素轻度认知障碍的严格检查也将代表该项目的新目标。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) most severely affects the fastest growing segment of our population: those age 80 and older. The ability to identify nondemented persons in a preclinical phase of AD will have far-reaching implications for both improved early diagnosis and use of anti-dementia pharmacologic therapies. Neuroprotective treatments will be most effective if applied at the earliest stages, which provides an important rationale for accurate preclinical detection. However, one of the remaining obstacles centers on the difficulty in identifying persons with AD before their deficits become clinically significant. Given the extent to which cognitive and brain changes associated with normal aging overlap with those of AD, the accurate detection of early AD in advanced age groups poses a number of unique challenges. We propose to conduct a five-year longitudinal study of the Very-Old (ages 80 and older) in which the combination of neuropsychological, neuroimaging, and genetic assessments will be examined, relative to the Young-Old (ages 60-79), in an effort to identify the most salient preclinical markers of AD. Our work during the previous project period has revealed important differences by age and genetic risk in the expression of cognitive and brain changes in clinical and preclinical AD. However, much remains to be done in characterizing the progression to AD in the Very-Old. Further clarification of the evolution of these brain and behavioral differences through the use of emerging neuropsychological (e.g., cognitive discrepancy measures) and functional magnetic resonance imaging (FMRI) techniques (e.g., combined arterial spin labeling/blood oxygen level dependent [ASL/BOLD] imaging) will advance our ability to understand the unique features associated with the development of AD in those at risk. Critical examination of another risk factor for AD conversion, mild cognitive impairment (MCI), will also represent a new aim for this project. Thus, the specific aims for this renewal period are (a) to determine the profile of spared and impaired cognitive processes associated with the preclinical phase of AD in the Very-Old, (b) to determine the clinical validity of a novel definitional scheme for MCI, its clinical outcomes, and whether differential rates of MCI and its various subtypes exist between Young-Old and Very-Old, (c) to use combined ASL/BOLD FMRI to measure functional changes within the medial temporal lobe (MTL) and related structures (e.g., parahippocampal gyrus, posterior cingulate) for the quantitative estimation of the cerebral metabolic rate of oxygen consumption (CMRO2) during episodic memory encoding, and (d) to integrate neuropsychological and neuroimaging methods to better determine the profile and progression of brain and behavioral changes indicative of the preclinical period of AD between the Young-Old and Very-Old. Public health relevance: Despite the many advances in neuropsychological and neuroimaging methods over the past decade, an effort focused on integrating these findings for prediction of progression to Alzheimer's disease (AD) has been lacking, particularly for our most susceptible segment of the population (i.e., those aged 80 and older). The proposed research addresses this gap and builds upon our experience in detailed neuropsychological studies along with advances with functional MRI studies of the medial temporal lobe for application to at-risk populations. With the increasing application of FMRI techniques to the study of AD, there is a growing need for quantitative measures that can more accurately reflect neural activity and its antecedent changes during the preclinical period of AD. The primary objectives of this project are to identify neuropsychological and neuroimaging changes in older adults at risk for the development of AD. Our specific aims continue the focus on our highest known risk group (i.e., those aged 80 and above) and on genetic susceptibility (e.g., apolipoprotein E). Critical examination of another risk factor for progression to AD, Mild Cognitive Impairment, will also represent a new aim for this project.