Memory Circuitry in MCI and Early Alzheimer's Disease

MCI 和早期阿尔茨海默病的记忆回路

• 批准号: 7644390
• 负责人: ANDREW J SAYKIN
• 金额: $ 33.06万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644390
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amygdaloid structure; Anatomy; Apolipoprotein E; Area; Automobile Driving; Basal Ganglia; Bilateral; Biological Markers; Brain; Brain imaging; Brain region; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Classification; Clinical; Cognition; Cognitive; Cohort Studies; Control Groups; Corpus Callosum; Data; Deltastab; Dementia; Detection; Deterioration; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Early Diagnosis; Early treatment; Elderly; Enrollment; Episodic memory; Functional Imaging; Functional Magnetic Resonance Imaging; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; Growth Factor; Hippocampus (Brain); Image; Impaired cognition; Individual; Individual Differences; Inferior frontal gyrus; Inflammatory; Interleukin-6; Knowledge; Lateral; Lead; Left; Literature; Magnetic Resonance Imaging; Measurement; Measures; Medial; Memory; Memory Loss; Memory impairment; Middle frontal gyrus structure; Modeling; Molecular; Nerve Degeneration; Neuropsychological Tests; Outcome; Parietal Lobe; Participant; Pathway interactions; Patients; Pattern; Performance; Pharmaceutical Preparations; Pharmacogenetics; Pilot Projects; Plasma; Positron-Emission Tomography; Prefrontal Cortex; Prevention strategy; Principal Investigator; Process; Proteins; Recruitment Activity; Request for Applications; Research; Research Personnel; Retrieval; Risk; Scanning; Semantic memory; Semantics; Shapes; Short-Term Memory; Signal Transduction; Staging; Structure; Superior temporal gyrus; System; Techniques; Temporal Lobe; Testing; Time; Tissues; Translating; Variant; Work; age related; base; cholinergic; clinical application; cognitive change; cohort; density; entorhinal cortex; falls; follow-up; frontal lobe; gray matter; high risk; imaging modality; improved; indexing; interest; mild neurocognitive impairment; neocortical; neuroimaging; neuroinflammation; neuromechanism; neuron loss; neurotransmission; novel; pre-clinical; programs; relating to nervous system; repaired; response; theories; treatment response

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.

描述（由申请人提供）：拟议的更新项目和其他项目已经表明，脑成像可以揭示临床前阶段记忆关键区域的异常，这是AD最早的缺陷区域。这一点很重要，因为正在制定的预防策略可能需要在痴呆症发作前至少5-10年实施，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%，是早期干预的关键人群。在最初的项目期间，我们招募，评估和扫描了一组50例MCI患者，50名有明显认知障碍（CC）的正常老年人，他们在认知测试中的功能正常，50名健康对照（HC）。初步分析表明，MCI患者在预测的大脑区域（海马和额叶皮质）的结构和功能变化，这些区域对胆碱能治疗有反应。几种假设途径的遗传变异可以部分解释基线时的区域变化和药物反应程度。重要的是，CC组在基线时显示出与MCI组惊人相似的模式，这表明在认知下降之前识别预测高风险的早期成像生物标志物的可行性。更新的目标是在总体模型的背景下继续跟踪达特茅斯记忆和衰老研究队列（基线后3、4.5和6年），该总体模型是在与遗传易感性标志物相关的综合纵向框架中最好地理解AD临床前阶段的结构、功能和认知。更新的具体目的是确定：（I）达特茅斯记忆和衰老队列的临床结局和先行预测因子，包括转换/进展率和（II）纵向认知变化的局部神经机制。补充的3 T MRI测量将包括关键记忆回路中组织完整性的形态测量指标，情景、工作和语义记忆的fMRI探针，以及连接性的DTI / fMRI测量。一个补充的目标代表了一个新的研究方向：（III）检查候选基因通路中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。这项研究将产生重要的神经影像学和遗传生物标志物的新信息，用于认知能力下降前的早期检测和治疗反应的评估。