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

揭示突触生物学、生活方式和认知弹性的交叉点

• 批准号: 10605265
• 负责人: Kaitlin B Casaletto
• 金额: $ 86.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605265
• 关键词: Address; Adult; Adverse effects; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid; Animal Experiments; Animals; Attenuated; Autopsy; Behavior; Behavioral; Biological; Biological Markers; Biology; Brain; Brain Pathology; Calcium; Calcium Signaling; Cell Adhesion; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Cessation of life; Clinical; Cognition; Cognitive; Cognitive aging; Collaborations; Communication; Coupled; Cytoskeleton; Data; Decision Making; Dementia; Development; Dissection; Dominant Genetic Conditions; Elderly; Etiology; Evaluation; Exercise; Frequencies; Goals; Health; Heterogeneity; Human; Human Biology; Impaired cognition; Individual; Infarction; Life; Life Style; Link; Liquid substance; Machine Learning; Maintenance; Mass Spectrum Analysis; Measurement; Measures; Memory; Modeling; Molecular; Monitor; Movement; Nature; Neurotransmitters; Participant; Pathology; Persons; Physical activity; Process; Proteins; Publishing; Research; Residual state; Resources; Role; Sampling; Signal Transduction; Symptoms; Synapses; Techniques; Technology; Time; Tissue Sample; Vesicle; Work; actigraphy; aged; aging brain; autosome; brain magnetic resonance imaging; brain tissue; clinically relevant; cognitive performance; cohort; design; emerging adult; end of life; human old age (65+); indexing; innovation; machine learning model; neural; neurobehavioral; neurogranin; neuronal pentraxin; neuropathology; postsynaptic; preservation; presynaptic; prevent; programs; promote resilience; prospective; protective factors; protein biomarkers; receptor; resilience; synaptic function; tau Proteins; theories; therapeutic candidate; therapeutic target

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.

项目摘要 /摘要 脑病理学在成年初开始积累，几乎在所有大脑中都可以检测到。然而， 认知衰老有显着的异质性，大多数老年人都没有证明认知能力 损害或痴呆症。揭示支持这种认知弹性的天然过程 神经病理学负担可能会产生有效的靶标，以预防或减缓阿尔茨海默氏病和相关的痴呆症 （ADRD）。我们假设维持的突触完整性和体育锻炼可能代表两个这样的 保护因素。突触交流是认知的基础基础。增加数据 建议保留的突触完整性可以支持临床功能，而不论存在病理学或 病因。此外，体育锻炼是一种高度含义的弹性行为，也与 动物的突触维护。我们的目标是确定可能是认知基础的突触生物学 人类的韧性和体育锻炼。我们将通过两个ADRC计划进行合作，以利用他们的 独特的优势。在Rush Memory和老化项目（R-MAP）中，来自动成年人的脑组织样品 遵循生命将用于量化> 150个突触蛋白标记物（n = 869）。在UCSF内存和老化中 中心（UC-MAC），纵向遵循的老年人的脑脊液样品将用于 量化七个突触蛋白标记物（n = 200）。这两个队列均完成纵向行为监测 体育活动水平的指数和全面的神经行为评估。认知的弹性会 作为神经病理学标记和认知表现之间的差异，被运行。瞄准一个 将确定深入的突触网络（R-MAP）和纵向，动态性质（UC-MAC） 突触标记和认知弹性。目标两个将应用创新的机器学习技术来识别 精确的Actraphy特征与深入的突触网络（R-MAP），纵向最牢固有关 突触标记变化（UC-MAC）和认知弹性（两者）。完成这些目标将 显着影响ADRD领域。我们旨在仔细识别突触和运动功能 使用最先进的测量技术，分析和 卓越的协作专业知识。该提案代表了两个国家ADRC之间的桥接 强有力地解决了高影响问题，而不是单独回答。