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

项目总结/摘要：阿尔茨海默病（AD）的病理生理过程-β- 淀粉样斑块和神经纤维缠结--比客观认知障碍早开始几十年， 出现临床痴呆的症状。这种“临床前”疾病阶段提供了一个窗口，了解早期 疾病机制以及AD病理学对认知老化的贡献。虽然工作跨越 不同的研究项目强调了淀粉样蛋白和tau蛋白测量在衰老队列中的重要性， 未来下降的预测因子，仍然难以预测个体受试者水平和机制的风险 与AD病理学在衰老中的初始后果相关的基因尚不清楚。我们的研究项目 包括尖端的神经成像（MRI，PET）和脑脊液分析，以了解神经元 记忆力下降的相关因素具体来说，我们建议利用一个预先存在的基线队列， 来自斯坦福大学记忆和衰老研究（SAMS）的临床上未受损（CU）的老年人，并且另外 提高这一队列的普遍性，30名新参与者自我认同为一个民族团体， 不是非西班牙裔白色人SAMS参与者之前完成了腰椎穿刺以收集脑脊液 液体（CSF），高分辨率功能MRI（在3 T）在视觉联想记忆范式，超高， 分辨率结构MRI（7 T），以评估内侧颞叶亚区的完整性，以及广泛的认知功能。 评估包括对依赖于记忆的记忆的多次测量。该提案将扩大 SAMS包括基线后7年的纵向访视（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 预期对完成SAMS基线访视的199名合格参与者中的150名进行数据收集。一 我们项目的优势在于强调依赖于大脑的记忆过程，因为神经系统 缠结病理在内嗅皮质和海马中常见，并且皮质tau沉积的初始部位 位于对视觉联想记忆回忆至关重要的皮层区域（角回和腹侧颞叶 皮质）。因此，我们很好地理解了量化（a）的结构和功能措施 内嗅和海马的完整性以及（B）记忆的海马依赖性机制（皮质 恢复）预测记忆衰退（目标1），并与区域tau PET（目标2）相关。考虑到所有的MRI和 在拟定的纵向第2波访视期间，将重复之前在基线时采集的生物液体测量值 在本应用中，我们还将检查这些创新成像中区域结构和功能变化 时间（目标3）。这项拟议的研究计划将产生有关特定领域的重要见解 记忆力衰退和衰老以及临床前AD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度量联合收割机，以确定一组 预测最相关的个体差异记忆老化和过渡到病理老化。

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.