Memory Circuitry in MCI and Early Alzheimer's Disease

MCI和早期阿尔茨海默病的记忆电路：早期检测和纵向变化的功能和形态测量MRI研究：记忆障碍是阿尔茨海默病（AD）最早和最显著的特征之一。结合结构和功能成像的研究可以揭示阿尔茨海默病记忆缺陷的大脑机制。迄今为止，使用功能MRI研究早期AD、衰老和对选择性记忆过程的影响的工作很少，也没有将功能MRI与体积和认知测量纵向结合的研究。符合轻度认知障碍（MCI）标准的患者在4年内发展为AD的风险接近50%。该项目的总体目标是通过新的事件相关fMRI记忆激活任务，MRI形态测量（海马，内嗅皮层[EC]和新皮质叶区）来测试MCI和轻度AD记忆障碍的神经解剖学机制模型，并表征纵向变化模式并确定与临床结果相关的疾病轨迹的基线预测因子。参与者：将包括25名轻度AD患者（CDR 1.0； NINDS/ADRDA标准），66名MCI患者（CDR 0.5），以及30名健康人口统计学匹配的对照组（年龄60-90岁，50%为女性）。方法：在研究1中，在项目1-3年期间，我们将从这3组中招募和研究新的患者，并进行横断面分析。在研究II中，在第2-5年期间，我们将每年重新研究MCI和对照受试者，使用重复测量设计评估进展的程度和模式。假设每年有15%的MCI转化为AD， 5%的损失率，我们将在研究结束时获得25名转化者、30名稳定的MCI患者和25名健康的老年人对照作为纵向分析的样本。所有受试者将有详细的临床和神经心理学特征，包括APOE和其他基因分析。每6个月或更短时间监测一次临床状态。成像将包括高分辨率t1加权体积MRI系列、T2轴向扫描、流量加权扫描和5个全脑回波平面语义、情景和工作记忆激活任务。多变量模型测试将用于纵向表征fMRI血流动力学激活、容量和记忆性能数据之间的关系模式，包括与遗传/神经保护因素和间隔期临床状态的关系。预期结果：我们最近对轻度阿尔茨海默病患者的研究显示，在额叶和颞叶新皮质区以及海马形成和EC中有几种异常的fMRI激活模式。在新的初步研究中，fMRI记忆探针可以区分健康老年人和轻度认知损伤。这项纵向研究将为MCI、早期AD和正常衰老的大脑结构、血流动力学激活和记忆提供重要的新信息，这些信息与开发新的神经保护剂的早期诊断、预后预测和治疗反应监测直接相关。

Memory Circuitry in MCI and Early Alzheimer's Disease: A Functional and Morphometric MRI Study of Early Detection and Longitudinal Change Rationale: Memory impairment is one of the earliest and most pronounced features of Alzheimer's Disease'(AD). Studies integrating structural and functional imaging can shed new light on brain mechanisms underlying memory deficits in AD. There is very little work to date using functional MRI to study early AD, aging, and effects on selective memory processes and no studies longitudinally integrating fMRI with volumetric and cognitive measures. Patients meeting criteria for Mild Cognitive Impairment (MCI) have a near 50 percent risk of developing AD within 4 years. The overall aims of this project are to test a model of the neuroanatomic mechanisms underlying memory impairment in MCI and mild AD using novel event-related fMRI memory activation tasks, MRI morphometry (hippocampus, entorhinal cortex [EC] and neocortical lobar regions), and to characterize longitudinal change patterns and identify baseline predictors of disease trajectory relevant to clinical outcome. Participants: will include 25 patients with mild AD (CDR 1.0; NINDS/ADRDA criteria), 66 patients with MCI (CDR 0.5), as well as 30 healthy demographically matched controls (ages 60-90, 50 percent female). Method: In Study I, during project years 1-3, we will enroll and study new patients from each of these 3 groups and perform cross- sectional analyses. In Study II, during years 2-5, we will restudy the MCI and control subjects annually to assess extent and pattern of progression using a repeated measures design. Assuming 15 percent MCI to AD conversion per year and 5 percent attrition we will have a sample of 25 converters, 30 stable MCI patients, and 25 healthy elderly controls by the end of the study for longitudinal analyses. All subjects will have detailed clinical and neuropsychological characterization including APOE and other genetic assays. Clinical status will be monitored every 6 months or less. Imaging will include a high resolution T1-weighted volumetric MRI series, T2 axial survey, flow-weighted scans, and 5 whole brain echo planar semantic, episodic and working memory activation tasks. Multivariate model testing will be employed to longitudinally characterize the pattern of relationships between fMRI hemodynamic activation, volumetric, and memory performance data including relationships with genetic/neuroprotective factors and interval clinical status. Expected Results: Our recent studies of mild AD patients show several patterns of abnormal fMRI activation in frontal and temporal neocortical sites and the hippocampal formation and EC. In new preliminary studies, fMRI memory probes have distinguished healthy elderly and MCI. The proposed longitudinal research will provide important new information on brain structure, hemodynamic activation and memory in MCI, early AD and normal aging that is directly relevant for early diagnosis, prediction of outcome, and monitoring of treatment response as new neuroprotective agents are developed.