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岁及以上的人群。在阿尔茨海默病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具有深远的意义。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依据。然而，仍然存在的障碍之一是在阿尔茨海默氏症患者的缺陷变得临床上显着之前难以识别他们。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程度重叠，在老年人群中准确检测早期阿尔茨海默病提出了许多独特的挑战。我们建议对高龄人群（80岁及以上）进行为期5年的纵向研究，结合神经心理学、神经影像学和遗传评估，与年轻老年人（60-79岁）进行比较，以确定阿尔茨海默病最显著的临床前标志物。我们在之前的项目期间的工作揭示了年龄和遗传风险在临床和临床前AD的认知和大脑变化表达方面的重要差异。然而，在描述老年痴呆症的进展方面还有很多工作要做。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）进一步阐明这些大脑和行为差异的演变，将提高我们理解与AD风险人群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）进行严格检查，也将是本项目的一个新目标。因此，这一更新期的具体目标是(a)确定与老年AD临床前阶段相关的未受损和受损认知过程的特征，(b)确定MCI新定义方案的临床有效性，其临床结果，以及MCI及其各种亚型在年轻-老年和老年之间是否存在差异。(c)使用ASL/BOLD FMRI联合测量内侧颞叶（MTL）及相关结构（如海马旁回、后扣带）内的功能变化，定量估计情景记忆编码过程中大脑耗氧量代谢率（cro2）；(d)整合神经心理学和神经影像学方法，以更好地确定阿尔茨海默病在年轻-老年和老年之间的临床前阶段的大脑和行为变化的特征和进展。公共卫生相关性：尽管神经心理学和神经影像学方法在过去十年中取得了许多进展，但将这些发现整合起来预测阿尔茨海默病（AD）进展的努力一直缺乏，特别是对于我们最易感的人群（即80岁及以上的人群）。拟议的研究解决了这一差距，并建立在我们详细的神经心理学研究经验的基础上，以及应用于高危人群的内侧颞叶功能MRI研究的进展。随着FMRI技术在阿尔茨海默病研究中的应用越来越多，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前兆变化的定量测量方法。该项目的主要目的是确定老年痴呆症风险人群的神经心理和神经影像学变化。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危险因素——轻度认知障碍的关键检查，也将代表这个项目的新目标。

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.