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

项目摘要/摘要 大脑病理在成年初期开始积累，到老年时几乎所有的大脑都能检测到。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。 损害或痴呆症。揭示支持这种认知弹性的自然发生的过程 神经病理负担可能产生预防或减缓阿尔茨海默病和相关痴呆的有效靶点 (ADRD)。我们假设，保持突触完整性和身体活动可能代表两种 保护性因素。突触交流是认知的基础。不断增加的数据 提示保留的突触完整性可能支持临床功能，而不管病理存在或 病因学。此外，体力活动是一种高度牵连的弹性行为，也与 动物的突触维持。我们的目标是确定可能构成认知基础的突触生物学。 人类的韧性和体力活动。我们将在两个ADRC项目中进行合作，以利用他们的 独一无二的优势。在快速记忆和衰老项目(R-MAP)中，尸检的成年人脑组织样本 随之而来的将用于量化&gt；150突触蛋白标记物(n=869)。加州大学旧金山分校的记忆和衰老 中心(UC-MAC)，纵向追踪活着的老年人的脑脊液样本将用于 定量检测7种突触蛋白标记物(n=200)。两个队列都完成了纵向肌动监测 体力活动水平指数和全面的神经行为评估。认知韧性将 可操作为神经病理标记物和认知表现之间的差异。目标一 将确定深度突触网络(R-MAP)和纵向、动态性质(UC-MAC)之间的关系 突触标记和认知韧性。目标二将应用创新的机器学习技术来识别 与深度突触网络(R-MAP)、纵向最密切相关的精确动作图功能 突触标记改变(UC-MAC)和认知弹性(两者)。实现这些目标将 对反兴奋剂领域产生重大影响。我们的设计是仔细识别突触和锻炼功能， 使用尖端测量技术、分析和 卓越的协作专业知识。这项提议是两个国家ADRC之间的桥梁， 有力地解决高影响力的问题，而不是任何一个人都能单独回答的问题。

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.