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

描述（由申请人提供）：记忆力下降是老年人的常见症状。大量文献指出，情节记忆（编码和随后检索事件记忆的能力）与年龄有关。海马体对情景记忆至关重要，它包括多个子领域，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，并表现出对年龄的不同脆弱性。特别是海马子区的选择性变化， 结构和功能可能驱动记忆表现中与年龄相关的变化，并且这些变化可能部分地与阿尔茨海默病（AD）病理学的临床前证据有关。高分辨率磁共振成像（MRI）的最新发展，包括（a）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7 T结构MRI，提供了一种在体内研究人类海马子场和检查海马记忆机制的方法。在这里，我们建议将这些创新的MRI技术应用于一个大型的，200人的健康老年人横断面人群（e 60岁），以检验以下中心假设：在老年人中，海马子区功能和结构的选择性变化驱动了模式分离和模式完成的机制性变化，其与年龄相关的联想回忆（情景记忆的中心形式）下降有关，并且部分地与临床前AD病理学有关。在目标1中，我们将使用hr-fMRI在3 T，沿着与代表性相似性分析和多体素模式分析，定量估计海马模式分离在编码和模式完成检索，与后者索引的皮层恢复，我们进一步的目的是将这些海马功能的定量措施，联想回忆和项目识别记忆性能。在目标2中，我们将使用高分辨率的结构MRI在7 T的海马子结构萎缩量化，我们将这些结构的措施，我们的定量hr-fMRI指数的模式分离和皮质恢复，以及记忆行为。在目标3中，我们将AD生物标志物（A β 42、tau和磷酸化tau蛋白）的脑脊液测定与hr-fMRI功能指标、7 T MRI海马子区结构指标和记忆行为相关。拟议研究的新奇和力量基于强大的初步数据，源于我们能够综合这些目标的数据，以发现功能，结构和早期病理学如何相互作用，影响衰老中的情景记忆。该项目可能最终为解决未受损老年人以及患有遗忘型轻度认知障碍和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 (e60 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.