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

描述（申请人提供）：记忆衰退是老年人的常见症状。大量文献指出，情景记忆（对事件进行编码并随后检索记忆的能力）的退化与年龄有关。海马体对情景记忆至关重要，它包括多个子区域，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，并对年龄表现出不同的脆弱性。特别是，海马亚区结构和功能的选择性改变可能驱动与年龄相关的记忆表现变化，这些变化可能部分与阿尔茨海默病（AD）病理的临床前证据有关。高分辨率磁共振成像（MRI）的最新发展，包括(a)高分辨率功能性MRI （hr-fMRI）结合强大的多变量分析方法和(b)超高场7T结构MRI，为研究人体海马亚区和研究海马记忆机制提供了一种手段。在这里，我们建议将这些创新的MRI技术应用于200名健康老年人（≥60岁）的大型横断面人群，以验证以下中心假设：在老年人中，海马亚区功能和结构的选择性变化驱动模式分离和模式完成的机制变化，这与联想回忆（情景记忆的一种中心形式）的年龄相关衰退有关，部分与临床前AD病理有关。在Aim 1中，我们将使用3T时的hr-fMRI，以及代表性相似性分析和多体素模式分析，定量估计编码时的海马模式分离和检索时的模式完成，后者通过皮质恢复来索引；我们进一步的目的是将这些海马功能的定量测量与联想回忆和项目识别记忆的表现联系起来。在Aim 2中，我们将在7T时使用高分辨率结构MRI来量化海马亚区结构萎缩，并将这些结构测量与模式分离和皮层恢复的定量hr-fMRI指数以及记忆行为联系起来。在Aim 3中，我们将把AD生物标志物（Abeta42、tau和磷酸化tau蛋白）的脑脊液检测与hr- fMRI功能指标、7T MRI海马亚场结构指标和记忆行为联系起来。该研究的新颖性和力量基于强大的初步数据，源于我们综合这些目标的数据的能力，以发现功能、结构和早期病理如何相互作用影响衰老过程中的情景记忆。该项目可能最终为解决未受损老年人以及患有遗忘性轻度认知障碍和AD的老年人与年龄相关的记忆衰退提供诊断和干预方法。

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.