High-resolution imaging of hippocampal mechanisms in age-related memory decline.

描述(申请人提供)：记忆力减退是老年人的常见症状。大量文献指出，与年龄相关的情节记忆(对事件进行编码并随后检索记忆的能力)会恶化。海马体对情景记忆至关重要，它由多个子区组成，被认为对模式分离和模式完成--记忆的基本机制--有不同的贡献，并表现出对年龄的不同脆弱性。特别是，海马区结构和功能的选择性变化可能会导致与年龄相关的记忆表现的变化，这些变化可能部分与阿尔茨海默病(AD)的临床前病理证据有关。高分辨率磁共振成像(MRI)的最新进展，包括(A)结合强大的多变量分析方法的高分辨率功能MRI(hr-fMRI)和(B)超高场7T结构MRI，为在体研究人类海马亚区和探讨海马记忆机制提供了手段。在这里，我们建议将这些创新的磁共振技术应用于一个大型的，200人的健康老年人(≥60岁)横截面人口来检验以下中心假设：在老年人中，海马子场功能和结构的选择性变化驱动模式分离和模式完成的机械性变化，这与年龄相关的联想记忆(情景记忆的一种中心形式)的下降有关，并部分与临床前AD病理有关。在目标1中，我们将使用3T的hr-fMRI以及代表性相似性分析和多体素模式分析来定量估计编码时的海马区模式分离和提取时的模式完成，后者以皮质恢复为索引；我们进一步的目标是将这些海马区功能的定量指标与联想记忆和项目识别记忆成绩联系起来。在目标2中，我们将使用7T的高分辨率结构磁共振来量化海马亚区结构萎缩，并将这些结构测量与我们的模式分离和皮质恢复的定量hr-fMRI指标以及记忆行为联系起来。在目标3中，我们将AD生物标志物(Abeta42、tau和pho-tau蛋白)的脑脊液分析与hr-fMRI功能指标、7T MRI海马子区结构指标和记忆行为相关联。这项拟议的研究以强大的初步数据为基础，其新颖性和力量来自于我们合成这些目标的数据的能力，以发现功能、结构和早期病理是如何相互作用影响衰老中的情景记忆的。该项目最终可能为诊断和干预方法提供信息，以解决未受损的老年人以及患有遗忘性轻度认知障碍和阿尔茨海默病的老年人与年龄相关的记忆下降问题。

DESCRIPTION (provided by applicant): Memory decline is a frequent symptom among aging adults. A substantial literature points to an age-related deterioration of episodic memory (the capacity to encode and subsequently retrieve memories for events). The hippocampus is critical for episodic memory, and comprises multiple subfields thought to contribute differentially to pattern separation and pattern completion - fundamental mechanisms of memory -- and to exhibit differential vulnerability to age. In particular, selective changes in hippocampal subfield structure and function may drive age-related changes in memory performance, and these changes may relate, in part, to preclinical evidence of Alzheimer's disease (AD) pathology. Recent developments in high-resolution magnetic resonance imaging (MRI), including (a) high-resolution functional MRI (hr-fMRI) combined with powerful multivariate analysis methods and (b) ultra-high field 7T structural MRI, provide a means to study human hippocampal subfields in vivo and to examine hippocampal mechanisms of memory. Here, we propose to apply these innovative MRI techniques to a large, 200-person cross-sectional population of healthy older adults (≥60 years) to test the following central hypothesis: In older adults, selective changes in hippocampal subfield function and structure drive mechanistic changes in pattern separation and pattern completion, which relate to age-related decline in associative recollection (a central form of episodic memory) and, in part, to preclinical AD pathology. In Aim 1, we will use hr-fMRI at 3T, along with representational similarity analysis and multivoxel pattern analysis, to quantitatively estimate hippocampal pattern separation at encoding and pattern completion at retrieval, with the latter indexed by cortical reinstatement; we further aim to relate these quantitative measures of hippocampal function to associative recollection and item recognition memory performance. In Aim 2, we will use high-resolution structural MRI at 7T to quantify hippocampal subfield structural atrophy, and we will relate these structural measures to our quantitative hr-fMRI indices of pattern separation and cortical reinstatement, as well as to memory behavior. In Aim 3, we will relate cerebrospinal fluid assays of AD biomarkers (Abeta42, tau, and phospho-tau proteins) to hr- fMRI functional metrics, 7T MRI hippocampal subfield structural metrics, and memory behavior. The novelty and power of the proposed research, which is grounded in strong preliminary data, derives from our ability to synthesize data across these Aims to discover how function, structure, and early pathology interact to affect episodic memory in aging. The project may ultimately inform diagnostic and intervention approaches for addressing age-related memory decline in unimpaired older adults, as well as those suffering from amnestic Mild Cognitive Impairment and AD.