Bridging cognitive aging in rodents to man using fMRI in amnestic MCI

使用 fMRI 在遗忘性 MCI 中弥合啮齿类动物与人类的认知衰老

• 批准号: 7845981
• 负责人: Michela Gallagher
• 金额: $ 65.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845981
• 关键词: Age; Aging; Alzheimer' s Disease; Animal Model; Animals; Antiepileptic Agents; Area; Brain imaging; Clinic; Clinical; Cognition; Cognitive aging; Cognitive deficits; Consensus; Crossover Design; Data; Dementia; Development; Diagnostic; Disease; Dose; Early Diagnosis; Elderly; Epilepsy; Family; Functional Magnetic Resonance Imaging; Functional disorder; Hippocampus (Brain); Human; Hyperactive behavior; Impaired cognition; Individual; Intervention; Levetiracetam; Light; Medial; Medical; Memory; Memory impairment; Modality; Modeling; Monitor; Neurocognitive; Neurons; Participant; Patients; Pattern; Performance; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebos; Prevalence; Production; Protocols documentation; Public Health; Rattus; Relative (related person); Reporting; Research; Research Personnel; Resolution; Retrieval; Risk Factors; Rodent; Role; Seizures; Signal Transduction; Specific qualifier value; Staging; System; Task Performances; Taxes; Temporal Lobe; Testing; Therapeutic Intervention; Time; TimeLine; Treatment Efficacy; Treatment Protocols; Validation; Work; aged; animal data; base; design; effective therapy; improved; man; meetings; mild neurocognitive impairment; mouse model; neuroimaging; novel; pre-clinical; prevent; public health relevance; relating to nervous system; response; restoration; stem; therapy development

DESCRIPTION (provided by applicant): This project will seize on new evidence that excess activity in the CA3 region of the hippocampus occurs both in aged animals with memory impairment and in patients with amnestic Mild Cognitive Impairment (aMCI), a condition that commonly precedes the development of AD. Treatments that target this excess activity in the preclinical animal model are effective in improving memory performance and in rescuing the ability of the targeted neurons to encode new information in memory. Because the CA3 dysfunction studied in animals can now be observed in high resolution functional neuroimaging (fMRI) in patients with aMCI and effective treatments in the preclinical setting have included compounds approved for use in man, here we will test whether a therapeutic intervention based on the animal model can lower excess activation in the CA3 and improve memory in aMCI. High-resolution fMRI will be conducted during a task that places demands on pattern separation, a memory function that specifically depends on the CA3 region. Recent work showed that aMCI patients have impaired memory on the pattern separation task and hyperactive BOLD signals in the CA3/DG during the conditions that tax pattern separation compared to age-matched controls. Significant negative correlations between performance on the target test items and hyperactivity during both encoding and retrieval suggest that excess CA3/DG activation is dysfunctional. The proposed study will experimentally test that hypothesis. The design will determine a treatment regimen that lowers hippocampal hyperactivity in aMCI and assess whether corresponding gains occur in memory performance in the pattern separation task, as predicted by research in the animal model. Participants on placebo and drug, counterbalanced within-subject, will also be tested outside the scanner with other assessments widely used to evaluate memory function. We have assembled an expert team of investigators and an external advisory group to guide this effort in an adaptive design with an exploratory phase (Year 1) and a confirmatory phase (Year 2). Findings from this project would have high impact as an experimental test of whether excess activity serves a compensatory function, as originally suggested in reports of increased hippocampal activation in MCI fMRI, or is in fact a dysfunctional condition, as demonstrated in the animal data. Because increased hippocampal activation in MCI also predicts further decline and progression to AD, the proposed research could be a first step in developing interventions that not only improve cognition in aMCI but also modify progression to AD. That approach is further encouraged by new data on excess neuronal activity in several mouse models of AD and prior research on the production of A beta driven by neural activity, observations that extend a role for excess activity in neurocognitive aging to a possible basis for aging as a primary risk factor for AD. In light of forecasts for a staggering burden of AD in the decades ahead if effective therapies are not found soon, this novel entry point for therapy at an early stage of cognitive impairment has great potential in a critical area of unmet medical need. PUBLIC HEALTH RELEVANCE: Aging is often associated with cognitive deficits, especially decline in memory functions. Aging is also the major risk factor for Alzheimer's Disease (AD), the most common form of dementia. This project will test a new modality of therapy directed at memory impairment in the elderly, which may also have potential to modify a transition from mild cognitive impairment to Alzheimer's disease. It will use tests of memory together with brain imaging to determine the effects of therapy in persons over the age of 55 who meet diagnostic criterion for amnestic mild cognitive impairment. )

描述（由申请人提供）：该项目将抓住新的证据，即海马CA 3区的过度活动发生在记忆障碍的老年动物和遗忘型轻度认知障碍（aMCI）患者中，这是一种通常先于AD发展的疾病。在临床前动物模型中靶向这种过度活性的治疗在改善记忆表现和挽救靶向神经元在记忆中编码新信息的能力方面是有效的。由于在动物中研究的CA 3功能障碍现在可以在aMCI患者的高分辨率功能性神经成像（fMRI）中观察到，并且临床前环境中的有效治疗包括批准用于人类的化合物，因此我们将测试基于动物模型的治疗干预是否可以降低CA 3的过度激活并改善aMCI的记忆。高分辨率的功能磁共振成像将在一项要求模式分离的任务中进行，模式分离是一种特别依赖于CA 3区域的记忆功能。最近的研究表明，aMCI患者在模式分离任务上的记忆受损，并且与年龄匹配的对照组相比，在征税模式分离的条件下，CA 3/DG中的BOLD信号过度活跃。在编码和提取过程中，目标测试项目的表现与多动之间存在显著的负相关性，表明过多的CA 3/DG激活是功能失调的。拟议的研究将通过实验验证这一假设。该设计将确定降低aMCI中海马活动过度的治疗方案，并评估模式分离任务中的记忆表现是否出现相应的增益，如动物模型研究所预测的那样。服用安慰剂和药物的参与者，在受试者内平衡，也将在扫描仪外进行测试，其他评估广泛用于评估记忆功能。我们已经组建了一个由研究人员组成的专家团队和一个外部咨询小组，以指导这项工作在一个具有探索阶段（第1年）和验证阶段（第2年）的适应性设计中进行。该项目的发现将具有很高的影响力，作为一个实验测试，过度活动是否具有代偿功能，如最初在MCI fMRI中海马激活增加的报告中所建议的那样，或者实际上是一种功能失调的情况，如动物数据所示。由于MCI中海马激活的增加也预示着进一步下降和进展为AD，因此拟议的研究可能是开发干预措施的第一步，这些干预措施不仅可以改善aMCI的认知，还可以改变AD的进展。这种方法进一步受到关于几种AD小鼠模型中过量神经元活动的新数据以及先前关于神经活动驱动的A β产生的研究的鼓励，这些观察结果将神经认知衰老中过量活动的作用扩展到衰老作为AD主要风险因素的可能基础。根据预测，如果不能很快找到有效的治疗方法，未来几十年AD的负担将是惊人的，这种在认知障碍早期阶段治疗的新切入点在未满足医疗需求的关键领域具有巨大潜力。 公共卫生相关性：衰老通常与认知缺陷有关，尤其是记忆功能下降。衰老也是阿尔茨海默病（AD）的主要风险因素，AD是最常见的痴呆症形式。该项目将测试一种针对老年人记忆障碍的新疗法，这种疗法也有可能改变从轻度认知障碍到阿尔茨海默病的转变。它将使用记忆测试和大脑成像来确定治疗对55岁以上符合遗忘性轻度认知障碍诊断标准的人的影响。)