Unraveling the intersection of synaptic biology, lifestyle, and cognitive resilience

项目总结/摘要 大脑病理学在成年早期开始积累，到老年时几乎所有大脑都可以检测到。然而， 认知老化具有显著的异质性，大多数老年人没有表现出认知老化的特征， 损伤或痴呆。揭示自然发生的过程，支持这种认知弹性， 神经病理学负担可能产生预防或减缓阿尔茨海默病和相关痴呆症的有效靶点 （ADRD）.我们假设，保持突触的完整性和身体活动可能代表了两个这样的 保护因素。突触通讯是认知的基础。提高统计数据 这表明，保存的突触完整性可以支持临床功能，而不管病理存在与否， 病因学此外，身体活动是一种高度牵连的弹性行为，也与 突触的维持。我们的目标是确定突触生物学可能是认知的基础 恢复力和身体活动的能力。我们将在两个ADRC项目中进行合作， 独特的优势在拉什记忆和衰老项目（R-MAP）中， 将使用在生活中随访的基因组来定量>150种突触蛋白标志物（n=869）。加州大学旧金山分校记忆与衰老 中心（UC-MAC），来自纵向随访的存活老年人的脑脊液样本将用于 定量7种突触蛋白标记物（n=200）。两个队列均完成纵向腕动计监测， 身体活动水平指数和全面的神经行为评估。认知弹性将 可以操作为神经病理学标志物和认知表现之间的差异。瞄准一号 将识别深度突触网络（R-MAP）和纵向，动态性质（UC-MAC）之间 突触标记和认知弹性。目标二将应用创新的机器学习技术来识别 精确的体动记录功能，最有力地涉及到深度突触网络（R-MAP），纵向 突触标志物变化（UC-MAC）和认知弹性（两者）。实现这些目标将 对ADRD领域产生重大影响。我们被设计来仔细识别突触和运动特征， 使用尖端的测量技术、分析技术支持持续的认知弹性， 卓越的协作专长。这项建议是两个国家发展成果中心与更多国家发展成果中心之间的桥梁。 强有力地解决了高影响力的问题，而不是单独回答。

PROJECT SUMMARY / ABSTRACT Brain pathology begins accumulating in early adulthood and is detectable in almost all brains by older age. Yet, there is remarkable heterogeneity in cognitive aging, and most aged adults do not evidence cognitive impairment or dementia. Uncovering the naturally occurring processes that support this cognitive resilience to neuropathology burden may yield potent targets to prevent or slow Alzheimer's disease and related dementias (ADRD). We hypothesize that maintained synaptic integrity and physical activity may represent two such protective factors. Synaptic communication is the foundational underpinning of cognition. Increasing data suggest that preserved synaptic integrity may support clinical functioning regardless of pathology presence or etiology. Further, physical activity is a highly implicated resilience behavior that has also been linked to synaptic maintenance in animals. Our goal is to determine the synaptic biology that may underlie cognitive resilience and physical activity in humans. We will collaborate across two ADRC programs to leverage their unique strengths. In the Rush Memory and Aging Project (R-MAP), brain tissue samples from autopsied adults followed in life will be used to quantify >150 synaptic protein markers (n=869). In the UCSF Memory and Aging Center (UC-MAC), cerebrospinal fluid samples from longitudinally followed living older adults will be used to quantify seven synaptic protein markers (n=200). Both cohorts complete longitudinal actigraphy monitoring as an index of physical activity levels, and comprehensive neurobehavioral assessments. Cognitive resilience will be operationalized as the discrepancy between neuropathology markers and cognitive performances. Aim one will identify the in-depth synaptic networks (R-MAP) and the longitudinal, dynamic nature (UC-MAC) between synaptic markers and cognitive resilience. Aim two will apply innovative machine learning techniques to identify precise actigraphy features that most robustly relate to in-depth synaptic networks (R-MAP), longitudinal synaptic marker changes (UC-MAC), and cognitive resilience (both). Accomplishing these aims will significantly impact the ADRD field. We are designed to carefully identify synaptic and exercise features that support sustained cognitive resilience using cutting edge measurement technologies, analytics, and exceptional collaborative expertise. This proposal represents a bridging between two national ADRCs to more powerfully address high impact questions than could be answered by either individually.