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: 7937985
• 负责人: Michela Gallagher
• 金额: $ 67.66万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937985
• 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，表明海马的CA3区域过多的活动既发生在具有记忆障碍的老年动物，又发生在具有柔滑的轻度认知障碍（AMCI）的患者中，这种情况通常是在AD发展之前。临床前动物模型中针对这种过多活动的治疗方法可有效改善记忆力表现，并挽救目标神经元在记忆中编码新信息的能力。因为现在可以在AMCI患者的高分辨率功能神经影像学（FMRI）中观察到在动物中研究的CA3功能障碍，并且在临床前环境中有效治疗的患者包括批准用于人类的化合物，我们将在这里测试基于CA3中动物模型的治疗干预措施是否可以降低CA3中的过量激活，并改善AMCI的内存并改善AMCI的内存。高分辨率功能磁共振成像将在对模式分离要求的任务中进行，这是一个特别取决于CA3区域的内存函数。最近的工作表明，与年龄匹配的对照相比，AMCI患者对模式分离任务的记忆力障碍，在税收模式分离的情况下，CA3/DG中的多动性大胆信号受损。在编码和检索过程中，目标测试项目的性能与多动症之间的显着负相关表明过量的CA3/DG激活功能失调。拟议的研究将通过实验检验该假设。该设计将确定一种治疗方案，该治疗方案降低了AMCI中海马过度活跃性，并评估在模式分离任务中的记忆表现中是否发生相应的收益，如动物模型中的研究所预测。安慰剂和药物的参与者，受试者内部的平衡，也将在扫描仪外测试其他评估，以评估记忆功能。我们组建了一个由调查人员组成的专家团队和一个外部咨询小组，以具有探索性阶段（1年）和确认阶段（第2年）的自适应设计指导这项工作。该项目的发现将具有很高的影响，作为对过量活动是否具有补偿功能的实验测试，如在MCI fMRI中增加的海马激活的报道，还是实际上是功能失调的状况，如动物数据所示。由于MCI中海马激活的增加也可以预测AD的进一步下降和进展，因此拟议的研究可能是开发干预措施的第一步，不仅可以改善AMCI的认知，而且还可以改变对AD的发展。在几种AD的小鼠模型中，有关过量神经元活动的新数据以及对神经活动驱动的β的生产，进一步的新数据，进一步鼓励了这种方法，这些观察结果将过量活动扩展到神经认知衰老中过量活动的作用，以作为作为AD的主要风险因素的衰老而可能的基础。鉴于未来几十年对AD负担的预测，如果未找到有效的疗法，那么在认知障碍的早期阶段，这种新颖的疗法入口处在未满足医疗需求的关键领域具有很大的潜力。 公共卫生相关性：衰老通常与认知缺陷有关，尤其是记忆功能的下降。衰老也是阿尔茨海默氏病（AD）的主要危险因素，这是痴呆症的最常见形式。该项目将测试针对老年人记忆障碍的新型治疗方式，这也可能有可能改变从轻度认知障碍到阿尔茨海默氏病的过渡。它将使用记忆测试以及大脑成像，以确定55岁以上符合诊断标准的患者的治疗作用。 ）