FMRI OF AT-RISK ELDERLY FOR ADZHEIMER'S DISEASE

阿尔茨海默氏病（AD）是未来几十年影响美国的最重要和最具挑战性的公共卫生问题之一。识别处于AD临床前阶段的老年人的能力将对改善早期诊断和使用认知增强药物疗法产生深远的影响。这种旨在减缓进展（“神经保护”）的治疗如果在发生显著神经元损失之前的最早阶段应用将是最有效的。然而，这种努力的剩余障碍之一集中在难以在早期AD患者的缺陷在临床上明显之前准确地鉴定其个体（即，在认知和功能下降之前）。我们建议招募并随访一组AD高危非痴呆老年人，以更好地检测和表征其临床前阶段。轻度认知功能障碍（MCI）和载脂蛋白E基因（APOE ε 4）的α 4等位基因的个体，都有显着升高的风险发展为AD。然而，MCI和APOE ε 4基因型本身不足以决定谁会发展为AD。我们建议进行一项为期五年的MCI和APOE相关风险的纵向研究，其中初始横断面功能性磁共振成像（fMRI）和遗传评估的组合将与纵向临床和神经心理学结果相结合，以确定AD的最显着的预测因子。根据我们的初步研究，我们预计，在情节记忆编码过程中，高风险老年人将表现出比低风险正常老年人更大程度的代偿性大脑活动，并且代偿性活动的程度将预测向AD的转化。在2（MCI与正常对照[NC]）× 2（APOE ε 4与非ε 4）设计中，我们将检查血氧水平依赖性（BOLD）脑激活 与各种大脑区域中的言语情景学习和回忆相关（例如，内侧颞叶、额叶、顶叶、后扣带回）。具体来说，拟议的研究将（a）检查MCI，APOE基因型和四组（即，MCI/ε 4; MCI/非ε 4; NC/ε 4; NC/非ε 4）;（B）确定APOE ε 4中的差异BOLD应答是否 人-如果存在-代表AD的预测因子，或者它存在于整个生命周期中，因此是独立于潜在AD发病机制的正常表型变体？后一个目的将通过检查APOE ε 4和非ε 4人群的横断面年轻成人样本来探索，以比较BOLD反应模式与老年人;（c）检查与情节编码相关的脑活动和其他重要临床活动（例如，情景记忆衰退的速度;向AD的转化），神经心理学（例如，临床记忆测量），和成像指数（例如，基于结构MRI的内侧颞叶体积;血液灌注的动脉自旋标记指数）。

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).