Cognitive Abilities of At-Risk Elderly for Dementia

描述(申请人提供)：阿尔茨海默病(AD)影响最严重的是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者的能力将对改进早期诊断和使用抗痴呆症药物疗法具有深远的影响。如果在早期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在AD患者的缺陷变得明显之前识别他们的困难。考虑到与正常衰老相关的认知和大脑变化与阿尔茨海默病的重叠程度，在高龄人群中准确检测早期阿尔茨海默病提出了一些独特的挑战。我们建议对高龄人群(80岁及以上)进行一项为期五年的纵向研究，结合神经心理学、神经影像和遗传学评估，以青年-老年人(60-79岁)为对照，努力确定AD最显著的临床前标志物。我们在前一个项目期间的工作发现，在临床和临床前AD中，认知和大脑变化的表达因年龄和遗传风险的不同而存在重要差异。然而，在描述老年痴呆症的发展过程方面，仍有许多工作要做。通过使用新兴的神经心理学(例如，认知差异测量)和功能磁共振成像(FMRI)技术(例如，联合动脉自旋标记/血氧水平依赖[ASL/BOLD]成像)进一步澄清这些大脑和行为差异的演变，将提高我们理解与高危人群AD发展相关的独特特征的能力。对AD转换的另一个风险因素--轻度认知障碍(MCI)的关键检查也将代表该项目的新目标。因此，这个更新期的具体目标是：(A)确定与极老年AD的临床前阶段相关的备用和受损的认知过程的概况；(B)确定新的MCI定义方案的临床有效性、其临床结果，以及MCI及其各种亚型在青年-老年和极老年之间是否存在差异性；(C)使用联合ASL/BOLD功能磁共振来测量内侧颞叶(MTL)和相关结构(例如，海马旁回，(D)整合神经心理学和神经成像方法，以更好地确定阿尔茨海默病(AD)临床前期在青年-老年和极老年之间的大脑和行为变化的概况和进展。与公共卫生相关：尽管神经心理学和神经成像方法在过去十年中取得了许多进展，但缺乏将这些研究结果集中起来预测阿尔茨海默病(AD)进展的努力，特别是对于我们人口中最敏感的部分(即80岁及以上的人)。这项拟议的研究解决了这一差距，并建立在我们在详细的神经心理学研究方面的经验，以及应用于高危人群的内侧颞叶功能磁共振研究的进展。随着功能磁共振成像技术在阿尔茨海默病研究中的应用日益增多，人们越来越需要能够更准确地反映阿尔茨海默病临床前期神经活动及其先期变化的定量方法。该项目的主要目标是确定老年痴呆症高危人群的神经心理学和神经影像改变。我们的具体目标继续侧重于我们已知的最高风险群体(即80岁及以上人群)和遗传易感性(例如载脂蛋白E)。对进展为阿尔茨海默病的另一个风险因素--轻度认知障碍--的关键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.