Memory Circuitry in MCI and Early Alzheimer's Disease

MCI 和早期阿尔茨海默病的记忆回路

基本信息

批准号：
8084137
负责人：
ANDREW J SAYKIN
金额：
$ 35.39万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8084137
关键词：
Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Amygdaloid structure Anatomy 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 Shapes Short-Term Memory Signal Transduction Staging Structure Superior temporal gyrus System Techniques Temporal Lobe Testing Time Tissues Translating Variant 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

项目摘要

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）：拟议的续订项目和其他项目表明，大脑成像可以揭示对记忆至关重要的区域的异常，这是临床前阶段中最早的AD赤字领域。这很重要，因为正在开发的预防策略可能需要在痴呆症发作开始前至少5 - 10年才能实现最大程度的有效性。有弱化的轻度认知障碍患者（MCI）在4年内患AD的风险约为50％，并且是早期干预的关键组。在最初的项目期间，我们招募，评估和扫描了50名MCI患者，50名正式老年人患有明显认知投诉（CC），他们在认知测试和50个健康对照（HC）的正常范围内发挥作用。初步分析显示，预测的大脑区域（海马和额叶皮层）中MCI患者的结构和功能变化，这些区域对胆碱能疗法做出了反应。几种假设的途径中的遗传变异可以部分解释基线时区域变化和药物反应程度。重要的是，CC组在基线时表现出与MCI组的非常相似的模式，这表明在认知下降之前可以识别早期成像生物标志物可预测高风险的可行性。更新的目的是在基准模型的背景下继续遵循达特茅斯记忆和老化研究队列（在基线后的3,4.5和6年），该模型可以最好地理解AD的临床前阶段中的结构，功能和认知，可以在综合纵向框架中可以理解，以与遗传性脆弱性标记有关。更新的具体目的是确定：（i）达特茅斯记忆和衰老队列中的临床结果和前述预测因子，包括转化率/进展率以及（ii）纵向认知变化的区域神经机制。互补的3T MRI度量将包括钥匙记忆电路中组织完整性的形态指标，fMRI的fMRI探针，工作和语义记忆以及DTI / FMRI连通性的指标。补充目的代表了一个新的研究方向：（iii）检查候选基因途径中等位基因变异对认知和神经轨迹和治疗反应的个体差异的贡献。这项研究将在认知下降和评估治疗反应之前产生有关神经影像学和遗传生物标志物的重要新信息。