Memory Circuitry in MCI and Early Alzheimer's Disease

描述(由申请人提供)：拟议的更新项目和其他项目表明，脑成像可以揭示临床前阶段对记忆至关重要的区域的异常，这是AD最早的缺陷区域。这一点很重要，因为可能需要在痴呆症发病前至少5-10年实施正在制定的预防战略，才能发挥最大的效果。遗忘型轻度认知障碍(MCI)患者在4年内发生AD的风险约为50%，是早期干预的重点人群。在最初的项目期间，我们招募、评估和扫描了50名MCI患者、50名有明显认知障碍(CC)、认知测试功能在正常范围内的愉悦老年人和50名健康对照(HC)。初步分析显示，MCI患者预测的大脑区域(海马体和额叶皮质)的结构和功能发生了变化，这些区域对胆碱能治疗有反应。几条假想途径的遗传变异可以部分解释基线和药物反应程度的区域变化。重要的是，CC组在基线上表现出与MCI组惊人的相似模式，这表明在认知能力下降之前识别预测高风险的早期成像生物标志物是可行的。更新的目标是在一个总体模型的背景下继续跟踪达特茅斯记忆和老龄化研究队列(基线后3、4.5和6年)，该模型可以在与遗传脆弱性标记相关的综合纵向框架中最好地理解阿尔茨海默病临床前阶段的结构、功能和认知。更新的具体目的是确定：(I)达特茅斯记忆和老龄化队列中的临床结果和预测因素，包括转换/进展率和(Ii)纵向认知变化的区域神经机制。补充的3T MRI测量将包括关键记忆回路中组织完整性的形态计量学指数，情景、工作和语义记忆的fMRI探针，以及连接的DTI/fMRI测量。一个补充目标代表了一个新的研究方向：(Iii)考察候选基因途径中的等位基因变异对认知和神经轨迹以及治疗反应的个体差异的贡献。这项研究将在神经影像和遗传生物标记物方面产生重要的新信息，用于在认知能力下降之前进行早期检测，并用于评估治疗反应。

DESCRIPTION (provided by applicant): The proposed renewal project and others have shown that brain imaging can reveal abnormalities in regions critical for memory, the area of earliest deficit in AD, during preclinical stages. This is important because prevention strategies under development will likely need to be implemented at least 5-10 years prior to onset of dementia to be maximally effective. Patients with amnestic Mild Cognitive Impairment (MCI) have ~ 50% risk of developing AD within 4 years and are a key group for early intervention. During the initial project period, we enrolled, assessed and scanned a cohort of 50 patients with MCI, 50 euthymic older adults with marked cognitive complaints (CC) who function within normal limits on cognitive testing and 50 healthy controls (HC). Preliminary analyses show structural and functional changes in MCI patients in predicted brain regions (hippocampus and frontal cortex) and that these regions responded to cholinergic therapy. Genetic variation in several hypothesized pathways could partially explain the regional changes at baseline and the degree of medication response. Importantly, the CC group showed a strikingly similar pattern to the MCI group at baseline, suggesting the feasibility of identifying early imaging biomarkers predictive of high risk prior to cognitive decline. The goal of the renewal is to continue to follow the Dartmouth Memory and Aging Study cohort (at 3,4.5 and 6 years after baseline) in the context of an overarching model that structure, function and cognition during the preclinical stages of AD can best be understood in an integrative longitudinal framework viewed in relation to genetic vulnerability markers. The Specific Aims of the renewal are to determine: (I) clinical outcomes and antecedent predictors in the Dartmouth Memory and Aging Cohort including conversion/ progression rates and (II) regional neural mechanisms underlying longitudinal cognitive changes. Complementary 3T MRI measures will include morphometric indices of tissue integrity in key memory circuits, fMRI probes of episodic, working and semantic memory, and DTI / fMRI measures of connectivity. A supplemental aim represents a new research direction: (III) to examine the contribution of allelic variation in candidate gene pathways to individual differences in cognitive and neural trajectory and treatment response. This study will yield important new information on neuroimaging and genetic biomarkers for early detection prior to cognitive decline and for assessment of treatment response.