Memory in Aging, Mild Cognitive impairment and AD

由一位新的独立研究人员提出的这项研究，旨在加深我们对随着年龄增长和记忆障碍患者记忆障碍的生理学基础的理解。我们将使用事件相关电位(ERPs)和功能磁共振成像(FMRI)来研究衰老、轻度认知障碍(MCI)和阿尔茨海默病(AD)的言语记忆过程。感兴趣的特定大脑电位是N400，这是刺激后近400毫秒达到峰值的负波，以及随后的晚期正波(LPC)。N400波幅对诱导词与其语义语境整合的难易程度很敏感。LPC一直与内存过程紧密相关。我们已经采用了我们的ERP单词重复范式，该范式在语义分类任务中利用重复的听觉上下文/视觉目标词对，用于fMRI。这一范式提供了内隐和外显言语记忆过程的电生理测量，并可能阐明这些过程的神经解剖学基础。我们的研究表明，健忘症患者对“一致”类别的样本词存在异常的事件相关电位重复效应(LPC重复效应)。这种减少的程度与陈述性记忆损害的严重程度有很好的相关性。我们最近发现，MCI患者的LPC单词重复效应也有所降低。此外，LPC重复效应幅度的严重降低似乎增加了随后转换为AD的可能性。我们的主要具体目标是：1)量化正常衰老时出现的ERP单词重复效应的下降。ERP单词重复效应的降低可能是记忆障碍和病理性脑老化的敏感迹象。2)测试我们的事件相关电位和功能磁共振范式对轻度AD和“临床前”AD的敏感性。3)提高我们对正常老年人和极早期AD患者N400和LPC产生的神经底物的理解。研究设计：病例对照、纵向研究和事件相关电位，结合功能磁共振研究和选定的行为测量。方法：正常受试者、MCI受试者和AD受试者在语义分类过程中获得事件相关电位和功能磁共振数据。重复性和一致性(与类别的匹配程度)将被系统地改变，以调节N400和LPC。将对N400和LPC的特征进行比较(组内和组内)，并与记忆和其他认知能力相关。事件相关的fMRI大胆反应模式将被用来约束N400和LPC神经世代的源偶极子模型。

The proposed studies, by a newly independent investigator, aim to further our understanding of the physiological bases of the memory impairments found with aging and in patients with memory disorders. We will use Event-Related Potentials (ERPs) and Functional-Magnetic Resonance Imaging (FMRI) to investigate verbal memory processes in aging, Mild Cognitive Impairment (MCI), and Alzheimer's disease (AD). The specific brain potentials of interest are the N400, a negativity which peaks near 400 msec post-stimulus, and the late positive component (LPC) which follows. The N400 amplitude is sensitive to the ease/difficulty with which the eliciting word is integrated with its semantic context. The LPC has been closely linked to memory processes. We have adapted our ERP word repetition paradigm, which utilizes repeating auditory context/visual target word pairs during a semantic categorization task, for use with FMRI. This paradigm provides electrophysiological measures of both implicit and explicit verbal memory processes, and may shed light on the neuroanatomical substrates of these processes. We have shown that amnesic patients have an abnormal reduced ERP repetition effect to "congruous" category-exemplar words (the "LPC repetition effect"). The degree of this reduction correlates well with severity of declarative memory impairment. We have recently found that patients with MCI also have a reduced LPC word repetition effect. Further, a severely reduced LPC repetition effect amplitude appears to increase the likelihood of subsequent conversion to AD. Our main specific aims are: 1) To quantify the decline in the ERP word repetition effects that occurs in normal aging. A reduced ERP word repetition effect may be a sensitive sign of memory impairment and pathological brain aging. 2) To test the sensitivity of our ERP and FMRI paradigms to mild AD and to "pre-clinical" AD. 3) To improve our understanding of which neural substrates generate the N400 and LPC in normal elderly and in patients with very early AD. Research design: Case-control and longitudinal studies and ERPs in conjunction with FMRI studies and selected behavioral measures. Methods: ERP and FMRI data will be obtained from normal, MCI, and AD subjects during semantic categorization. Repetition and congruity (degree of fit with a category) will be varied systematically to modulate the N400 and LPC. Comparisons of N400 and LPC characteristics will be made (between-and within- group) and related to memory and other cognitive abilities. Event-related FMRI BOLD response patterns will be used to constrain source dipole models for the neural generations of the N400 and LPC.