Hippocampal-dependent memory decline in aging and early Alzheimer's disease

项目摘要/摘要：阿尔茨海默病(AD)的病理生理过程 淀粉样斑块和神经原纤维缠结--在客观认知障碍和 存在临床痴呆症的症状。这一“临床前”疾病阶段提供了一扇了解早期的窗口 疾病机制以及阿尔茨海默病病理对认知老化的贡献。尽管在工作中 不同的研究计划强调了淀粉样蛋白和tau测量在老年队列中的重要作用 未来下降的预测因素，但仍然很难预测个体主体层面和机制的风险 与AD病理在衰老中的最初后果相关的尚不清楚。我们的研究计划 涉及尖端神经成像(MRI、PET)和脑脊液分析，以了解神经元 记忆力衰退的相关因素。具体地说，我们建议利用先前存在的199名老年人的基线队列 斯坦福记忆和老龄化研究(SAMS)的临床未受损(CU)老年人，以及 通过30名新参与者提高该队列的泛化能力，这些参与者自我认同于 不是非西班牙裔白人。SAMS参与者之前完成了腰椎穿刺术以收集脑脊液 流体(CSF)，高分辨率功能磁共振(3T)，在视觉联想记忆范例中，超高 分辨率结构磁共振成像(7T)评估内侧颞叶亚区的完整性和广泛的认知 评估包括对海马区依赖记忆的多项测量。这项提案将延长 SAMS将包括基线后7年的纵向访问(第2波)，重复基线模式，以及 将tau PET与下一代配体18F-PI-2620结合。除了丰富基线样本外，我们还 预期收集完成SAMS基线访问的199名合格参与者中的150名的数据。一个 我们计划的优点是强调海马体依赖的记忆过程，因为 缠结病理常见于内嗅皮层和海马区，皮质tau沉积的起始部位。 位于对视觉联想记忆至关重要的皮质区域(角回和腹侧颞叶 大脑皮层)。因此，我们能够很好地理解结构和功能措施如何量化(A) 内嗅觉和海马体的完整性以及(B)海马体依赖的记忆机制(大脑皮层 恢复)预测记忆衰退(目标1)，并与区域tau PET有关(目标2)。鉴于所有的核磁共振和 之前在基线收集的生物流体测量将在建议的纵向波2访问期间重复进行 在这项应用中，我们还将检查这些创新成像中的区域结构和功能变化 随时间推移的措施(目标3)。这项拟议的研究计划将产生关于特定问题的关键见解 衰老和临床前阿尔茨海默病记忆衰竭和衰退的潜在机制。最终目标是制定 全面的多变量模型，将结合我们的深度表型指标来确定 与衰老和向病理性衰老过渡的记忆的个体差异最相关的预测因子。

PROJECT SUMMARY/ABSTRACT: The pathophysiological processes of Alzheimer’s disease (AD) –– beta- amyloid plaques and neurofibrillary tangles –– begin decades before objective cognitive impairment and symptoms of clinical dementia are present. This “preclinical” disease stage offers a window to understand early disease mechanisms as well as the contributions of AD pathology to cognitive aging. Although work across different research programs highlights the utility of amyloid and tau measurements in aging cohorts as important predictors of future decline, it remains difficult to predict risk at the individual subject level and mechanisms associated with the initial consequences of AD pathology in aging remain unclear. Our research program involves cutting-edge neuroimaging (MRI, PET) and cerebrospinal fluid analysis to understand the neuronal correlates of memory decline. Specifically, we propose to leverage a pre-existing baseline cohort of 199 older clinically unimpaired (CU) older adults from the Stanford Memory and Aging Study (SAMS), and additionally improve the generalizability of this cohort with 30 new participants that self-identify in an ethnoracial group that is not non-Hispanic White. SAMS participants previously completed lumbar puncture to collect cerebrospinal fluid (CSF), high-resolution functional MRI (at 3T) during a visual associative memory paradigm, ultra high- resolution structural MRI (at 7T) to assess medial temporal lobe subregion integrity, and extensive cognitive assessment including multiple measurements of hippocampal-dependent memory. This proposal will extend SAMS to include a longitudinal visit 7 years after baseline (Wave 2) that repeats baseline modalities, and incorporates tau PET with a next generation ligand 18F-PI-2620. In addition to enriching the baseline sample, we anticipate data collection on 150 of the 199 eligible participants that completed the baseline visits for SAMS. A strength of our program is the emphasis on hippocampal-dependent memory processes, given that neurofibrillary tangle pathology is common in entorhinal cortex and hippocampus, and the initial sites of cortical tau deposition are in cortical areas critical for visual associative memory recollection (angular gyrus and ventral temporal cortex). Thus, we are well positioned to understand how structural and functional measures that quantify (a) entorhinal and hippocampal integrity as well as (b) hippocampal-dependent mechanisms of memory (cortical reinstatement) predict memory decline (Aim 1) and relate to regional tau PET (Aim 2). Given that all MRI and biofluid measures previously collected at baseline will be repeated during the longitudinal Wave 2 visit proposed in this application, we will also examine regional structural and functional change in these innovative imaging measures over time (Aim 3). This proposed research program will yield critical insights regarding the specific mechanisms underlying memory failure and decline in aging and preclinical AD. The ultimate goal is to formulate comprehensive multivariate models that will combine our deep phenotyping metrics to determine the set of predictors most relevant for individual differences in memory in aging and the transition to pathological aging.