FMRI OF AT-RISK ELDERLY FOR ADZHEIMER'S DISEASE

阿尔茨海默病(AD)是未来几十年将影响这个国家的最重要和最具挑战性的公共卫生问题之一。识别处于阿尔茨海默病临床前阶段的老年人的能力将对改进早期诊断和使用认知增强药物疗法具有深远的影响。这种旨在减缓进展的治疗(“神经保护”)如果在重大神经元丢失发生之前的最早阶段应用将是最有效的。然而，这些努力的剩余障碍之一是在临床表现出缺陷之前(即认知和功能下降之前)准确识别早期阿尔茨海默病患者的困难。我们建议招募和跟踪一组AD高危的非痴呆老年人，以努力更好地发现和描述其临床前阶段。轻度认知障碍(MCI)患者和携带载脂蛋白E基因epsilon-4等位基因(ApoE Epsilon4)的患者患AD的风险均显著增加。然而，仅有MCI和APOE epsilon 4基因不足以决定谁会患上AD。我们建议对MCI和APOE相关风险进行一项为期五年的纵向研究，将初始横断面功能磁共振成像(FMRI)和遗传学评估与纵向临床和神经心理学结果相结合，努力确定AD最显著的预测因素。根据我们的初步研究，我们预计高危老年人在情景记忆编码过程中表现出比低风险正常老年人更大程度的代偿大脑活动，代偿活动的程度将预测转换为AD。在2(MCI与正常对照[NC])×2(APOE epsilon 4与非epsilon 4)设计中，我们将检查血氧水平依赖(BOLD)的脑激活 与大脑不同区域(例如，内侧颞叶、额叶、顶叶、后扣带回)的言语情景学习和回忆有关。具体地说，这项研究将(A)在四组(即MCI/epsilon 4；MCI/非epsilon 4；NC/epsilon 4；NC/非epsilon 4)中考察MCI、APOE基因和脑信号强度之间的关系；(B)确定APOE epsilon 4中是否存在差异的BOLD反应 人--如果存在--代表AD的预测因子，或者它在整个生命周期中存在，因此是一个独立于潜在AD发病机制的正常表型变异？后一个目标将通过检查APOE epsilon 4和非epsilon 4人的横断面样本来探索，以比较老年人的大胆反应模式；以及(C)检查与情景编码相关的脑活动与其他重要临床指标(例如情景记忆减退率；转换为AD)、神经心理学(例如临床记忆测量)和成像指标(例如基于结构MRI的内侧颞叶体积；血液灌流的动脉自旋标记指数)之间的相互作用。

Alzheimer's disease (AD) represents one of the most important and challenging public health concerns that will affect this country in the coming decades. The ability to identify older adults who are in a preclinical phase of AD will have far-reaching implications for both improved early diagnosis and use of cognitive enhancing pharmacologic therapies. Such treatments aimed at slowing progression ("neuroprotection") will be most effective if applied at the earliest stages before significant neuronal losses have occurred. However, one of the remaining obstacles to such efforts centers on the difficulty in accurately identifying individuals with incipient AD before their deficits are clinically apparent (i.e., prior to both cognitive and functional decline). We propose to recruit and follow a group of nondemented older adults at high risk for AD in an effort to better detect and characterize its preclinical stage. Individuals with mild cognitive impairment (MCI), and individuals with the epsilon-4 allele of the apolipoprotein E gene (APOE epsilon4), both have significantly elevated risks of developing AD. However, MCI and APOE epsilon4 genotype alone are insufficient in determining who will develop AD. We propose to conduct a five-year longitudinal study of MCI- and APOE-related risk in which the combination of initial cross-sectional functional magnetic resonance imaging (fMRI) and genetic assessments will be combined with longitudinal clinical and neuropsychologic outcomes in an effort to identify the most salient predictors of AD. Based on our preliminary studies, we expect that at-risk older adults will exhibit a greater degree of compensatory brain activity during episodic memory encoding than will low-risk normal older adults, and the degree of compensatory activity will be predictive of conversion to AD. In a 2 (MCI vs. normal control [NC]) x 2 (APOE epsilon4 vs. non-epsilon4) design, we will examine blood oxygen level dependent (BOLD) brain activation associated with verbal episodic learning and recall in a variety of brain regions (e.g., medial temporal, frontal, parietal, posterior cingulate). Specifically, the proposed study will (a) examine the relationship between MCI, APOE genotype, and brain signal intensities during episodic memory encoding in the four groups (i.e., MCI/epsilon4; MCI/non-epsilon4; NC/epsilon4; NC/non-epsilon4); (b) determine whether a differential BOLD response in APOE epsilon4 persons--if present--represents a predictor of AD, or is it present across the life span and therefore a normal phenotypic variant independent of underlying AD pathogenesis? This latter aim will be explored by the examination of a cross-sectional young adult sample of APOE epsilon4 and non-epsilon4 persons for comparison of BOLD response patterns to the older adults; and (c) examine for interactions between episodic encoding-related brain activity and other important clinical (e.g., rate of episodic memory decline; conversion to AD), neuropsychologic (e.g., clinical memory measures), and imaging indices (e.g., structural MRI-based medial temporal lobe volumes; arterial spin labeling indices of blood perfusion).