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

描述（由申请人提供）：该项目将抓住新的证据，证明海马CA3区域的过度活动发生在有记忆障碍的老年动物和患有遗忘性轻度认知障碍（aMCI）的患者中，这种情况通常发生在AD的发展之前。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表现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，因此我们将在这里测试基于动物模型的治疗干预是否可以降低CA3的过度激活并改善aMCI的记忆。高分辨率fMRI将在需要模式分离的任务中进行，模式分离是一种特别依赖于CA3区域的记忆功能。最近的研究表明，与年龄匹配的对照组相比，在模式分离条件下，aMCI患者在模式分离任务中的记忆受损，CA3/DG中的BOLD信号异常活跃。在编码和检索过程中，目标测试项目的表现与过度活跃之间存在显著的负相关，这表明过度的CA3/DG激活是功能失调的。拟议中的研究将通过实验验证这一假设。该设计将确定一种治疗方案，降低aMCI中海马的过度活动，并评估在模式分离任务中是否会出现相应的收益，正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，在受试者内部进行平衡，还将在扫描仪外接受其他广泛用于评估记忆功能的评估。我们已经组建了一个专家调查小组和一个外部咨询小组，在探索阶段（第一年）和确认阶段（第二年）的适应性设计中指导这项工作。该项目的研究结果将对实验测试产生重大影响，以确定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状态，如动物数据所证明的那样。由于MCI中海马激活的增加也预示着进一步的衰退和向AD的进展，因此提出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，还可以改变AD的进展。这一方法得到了进一步的支持，新数据显示，在几种AD小鼠模型中，神经元活动过度，以及先前对神经活动驱动的A β产生的研究，这些观察结果将过度活动在神经认知衰老中的作用扩展到衰老作为AD主要危险因素的可能基础。如果不能很快找到有效的治疗方法，人们预计在未来几十年里，阿尔茨海默病的负担将会非常沉重。因此，在认知障碍的早期阶段，这一新的治疗切入点在未满足医疗需求的关键领域具有巨大的潜力。

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. )