1H and 31P MR Spectroscopy of Hippocampal Hyperactivity in Aging and MCI

 描述（由申请人提供）：我们的记忆随着年龄的增长而变化。阿尔茨海默病相关的记忆力下降本身代表了一个重大的公共卫生影响，但认知能力下降-特别是记忆力下降-已被证明是阿尔茨海默病（AD）的一个重要风险因素。检查神经认知老化将帮助我们更好地表征整个生命周期中大脑的病理和非病理变化，并确定认知衰退的临床前标志物。该提案的目标是测试衰老和遗忘型轻度认知障碍（aMCI）的神经认知模型的关键预测，该模型表明MTL结构内的连接和活动变化是记忆中行为缺陷的基础。特别是，在啮齿动物和人类的研究中，海马体表现出“过度活跃”--一种潜在的功能失调状态，与从成功的记忆辨别（源自模式分离并导致对细节的准确记忆）到过度概括（源自模式完成）的行为转变有关。为此，使用低剂量抗癫痫药减少aMCI中的这种过度活动与记忆辨别任务中的表现改善相关，我们已经多次使用记忆辨别任务来索引海马功能和年龄相关变化以及aMCI相关变化。由于没有直接记录啮齿动物的多动症，人类研究往往依赖于BOLD功能磁共振成像提供的间接和相对测量。在这里，我们提出了一个有针对性的，新颖的，代谢的神经通路负责这种多动症的调查，以确定啮齿动物模型的适用性。使用磁共振成像光谱（MRS）和代谢物成像方法，我们的目标是测量兴奋性和抑制性活性（例如GABA，谷氨酸，胆碱等）的代谢特征，验证海马过度活跃是由于海马内CA 3复发侧支的抑制释放引起的假设，当海马积极处理新信息时，导致兴奋性活动增加和抑制性活动减少。我们建议使用两种MRS扫描，1H-MRS和31 P-MRS来确定哪种扫描对这种过度活动更敏感。最后，我们将评估这些多动的MRS测量是否与几种海马-海马依赖性记忆任务的表现呈反比关系，已知这些记忆任务对衰老和MCI敏感。

 DESCRIPTION (provided by applicant): Our memory changes as we age. Age-related memory decline in and of itself represents a significant public health impact, but cognitive decline - and in particular memory decline - has been shown to be an important risk factor for Alzheimer's Disease (AD). Examining neurocognitive aging will help us better characterize pathological and non-­pathological changes in the brain throughout the lifespan and identify preclinical markers for cognitive decline. The goal of this proposal is to test key predictions of neurocognitive model of aging and amnestic Mild Cognitive Impairment (aMCI) that suggests changes in connectivity and activity within structures in the MTL underlie behavioral deficits in memory. In particular, in both rodent and human studies, the hippocampus exhibits "hyperactivity" - a potentially dysfunctional state that has been tied to behavioral shifts away from successful mnemonic discrimination (derived from pattern separation and leading to accurate memory for details) and towards over-­generalization (derived from pattern completion). To this end, reduction of this hyperactivity in aMCI using a low-­dose antiepileptic s associated with improved performance in a mnemonic discrimination task that we have used many times to index hippocampal function and age-­ and aMCI-­related changes. Without the direct recording of hyperactivity possible in rodents, human studies have often relied on the indirect and relative measures provided by BOLD fMRI. Here, we propose a directed, novel, metabolic investigation into the neuronal pathways responsible for this hyperactivity to determine the applicability of the rodent model. Using magnetic resonance imaging spectroscopy (MRS) and metabolite imaging methods, we aim to measure the metabolic signatures for excitatory and inhibitory activity (e.g. GABA, glutamate, choline, etc.), testing th hypothesis that hippocampal hyperactivity arises from the release of inhibition on the CA3 recurrent collaterals within the hippocampus, leading to an increase in excitatory activity and a decrease in inhibitory activity when the hippocampus is actively processing new information. We propose utilizing two MRS scans, 1H-­MRS and 31P-­MRS to determine which scan is more sensitive to this hyperactivity. Finally, we will evaluate if these MRS measures of hyperactivity have an inverse relationship with performance on several hippocampal-­dependent memory tasks, known to be sensitive to aging and MCI.