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

描述(由申请人提供)：这个项目将抓住新的证据，即海马区CA3区的过度活动在患有记忆障碍的老年动物和遗忘性轻度认知障碍(AMCI)患者中都会发生，遗忘性轻度认知障碍(AMCI)通常是AD发展的先兆。在临床前动物模型中针对这种过度活动的治疗在改善记忆性能和挽救目标神经元在记忆中编码新信息的能力方面是有效的。由于在动物身上研究的CA3功能障碍现在可以在aMCI患者的高分辨率功能神经成像(FMRI)中观察到，并且在临床前环境中的有效治疗包括被批准在人类使用的化合物，在这里，我们将测试基于动物模型的治疗干预是否可以降低aMCI患者CA3的过度激活并改善记忆。高分辨率功能磁共振成像将在对模式分离提出要求的任务期间进行，模式分离是一种特别依赖于CA3区的记忆功能。最近的研究表明，与年龄匹配的对照组相比，aMCI患者在模式分离的条件下，在模式分离任务上的记忆受损，在CA3/DG中存在过度活跃的BOLD信号。在目标测试项目上的表现与编码和提取过程中的多动之间存在显著的负相关，这表明CA3/DG的过度激活是功能失调的。这项拟议的研究将在实验上验证这一假设。该设计将确定一种治疗方案，以降低aMCI中的海马体过度活动，并评估在模式分离任务中是否如动物模型研究所预测的那样，在记忆表现方面出现相应的改善。服用安慰剂和药物、在受试者内部保持平衡的参与者也将在扫描仪外接受测试，其他评估被广泛用于评估记忆功能。我们已经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，以指导适应性设计的工作，包括探索阶段(第1年)和确证阶段(第2年)。这个项目的发现将产生很大的影响，作为一项实验测试，过度活动是起到补偿功能的作用，正如最初在MCI功能磁共振成像中关于海马区激活增加的报告所建议的那样，或者实际上是一种功能失调的情况，如动物数据所证明的那样。由于MCI的海马区激活增加也预示着AD的进一步衰退和进展，这项拟议的研究可能是开发干预措施的第一步，该干预不仅可以改善AMCI的认知，还可以改变AD的进展。关于几个AD小鼠模型中神经元过度活动的新数据，以及之前关于神经活动驱动的Aβ产生的研究，进一步鼓励了这种方法，观察到过度活动在神经认知老化中的作用延伸到衰老作为AD主要风险因素的可能基础上。根据预测，如果不尽快找到有效的治疗方法，未来几十年AD将带来惊人的负担，这种在认知障碍早期阶段进行治疗的新切入点在一个未得到满足的医疗需求的关键领域具有巨大的潜力。 与公共健康相关：衰老通常与认知缺陷有关，特别是记忆功能的下降。衰老也是阿尔茨海默病(AD)的主要危险因素，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55岁以上符合遗忘性轻度认知障碍诊断标准的人的治疗效果。)

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. )